Physiological and pathophysiological actions of insulin in the liver

Abstract

The liver plays an important role in the control of glucose homeostasis. When insulin levels are low, such as in the fasting state, gluconeogenesis and glycogenolysis are stimulated to maintain the blood glucose levels. Conversely, in the presence of increased insulin levels, such as after a meal, synthesis of glycogen and lipid occurs to maintain the blood glucose levels within normal range. Insulin receptor signaling regulates glycogenesis, gluconeogenesis and lipogenesis through downstream pathways such as the insulin receptor substrate (IRS)-phosphoinositide 3 (PI3) kinase-Akt pathway. IRS-1 and IRS-2 are abundantly expressed in the liver and are thought to be responsible for transmitting the insulin signal from the insulin receptor to the intracellular effectors involved in the regulation of glucose and lipid homeostasis. Impaired insulin receptor signaling can cause hepatic insulin resistance and lead to type 2 diabetes. In the present study, we focus on a concept called “selective insulin resistance,” which has received increasing attention recently: the frequent coexistence of hyperglycemia and hepatic steatosis in people with type 2 diabetes and obesity suggests that it is possible for the insulin signaling regulating gluconeogenesis to be impaired even while that regulating lipogenesis is preserved, suggestive of selective insulin resistance. In this review, we review the progress in research on the insulin actions and insulin signaling in the liver.

Introduction

The liver plays an important role in the control of nutrient homeostasis. It has the ability to synthesize glucose (gluconeogenesis) and glycogen (glycogenesis), and also to convert glucose into fatty acids (lipogenesis), which are subsequently esterified with glycerol to form triacylglycerol. Triacylglycerol is packaged with cholesterol, phospholipids and proteins to form very low density lipoprotein (VLDLs) and secreted from the liver [1, 2].

Insulin plays a crucial role in the regulation of glycogenesis, gluconeogenesis, and lipogenesis in the liver [3]. When the level of blood glucose rises after a meal, insulin is secreted from the pancreas. Insulin binds to the insulin receptor, initiating insulin signaling, and becomes internalized in the cells along with its receptor. Approximately 50% of the secreted insulin in the body is degraded in the liver by the insulin-degrading enzyme, insulinase, and lysosomal enzymatic processes [4, 5]. In fact, the ratio of insulin to C-peptide, which is a cleavage product of proinsulin that is produced at a 1:1 molar ratio to insulin, in the blood was reported as being significantly increased in liver-specific insulin receptor-deficient (LIRKO) mice [6]. Insulin receptor signaling through pathways downstream of the insulin receptor, such as the insulin receptor substrate (IRS)-phosphoinositide 3 (PI3) kinase-Akt pathway, is known to regulate glycogenesis, gluconeogenesis, and lipogenesis [7]. Especially, IRS-1 and IRS-2 are abundantly expressed in the liver [8-10] and are thought to be responsible for transmitting the insulin signal from the insulin receptor to the intracellular effectors involved in the regulation of glucose and lipid homeostasis.

Impaired insulin receptor signaling can cause hepatic insulin resistance, leading to metabolic syndrome and type 2 diabetes [11]. The coexistence of hyperglycemia and hepatic steatosis in many people with these diseases [12, 13] suggests that it is possible for the insulin signaling pathway regulating gluconeogenesis to be impaired even while that leading to lipogenesis is preserved. This phenomenon, referred to as “selective insulin resistance,” [14] has received increasing attention recently. In this review, we focus on the progress in research on the physiological and pathophysiological roles of insulin signaling in the liver.

1. Insulin receptor signaling in the liver

The insulin receptor consists of two α-subunits and two β-subunits linked to each other by disulfide bonds. Insulin binds to the extracellular α-subunits of the insulin receptor, which results in autophosphorylation of the tyrosine residues of the intracellular β-subunits [7, 15]. Autophosphorylation of the insulin receptor increases its tyrosine kinase activity, which leads to phosphorylation of the IRSs via their phosphotyrosine-binding (PTB) domains [8]. Although several isoforms of IRS have been identified, including IRS-1, -2, -3, -4, -5, and -6 [9, 10, 16-19], IRS-1 and IRS-2 constitute the main IRS isoforms expressed in the liver [20-22]; IRS-6 is almost not detectable at all in the liver [19]. PI3 kinase is recruited via two internal src homology 2 (SH2) domains to site-specific phosphotyrosine residues on the cytoplasmic tails of the IRSs. PI3 kinase catalyzes the formation of the lipid second messenger phosphatidylinositol-3,4,5-triphosphate and activates 3-phosphoinositide-dependent protein kinase 1 (PDK1) [23]. PDK1 activates Akt/protein kinase B (Akt/PKB), of which there are three isoforms: Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ [24, 25]. Phosphorylation of Akt at Thr308 by PDK1 and at Ser473 by mTOR2, leads to phosphorylation of AKT substrates such as GSK3β, FoxO1, BAD, PDE3B, and TSC2, which promotes glucose metabolism, proliferation, growth, and translation, but impairs lipolysis and apoptosis [26]. Although Akt1 and Akt2 are prominently expressed in various tissues, including classical insulin-sensitive tissues like the liver and muscle, Akt3 expression is restricted to the testes, brain, lung, and fat [27-29]. Akt1-deficient mice show impaired fetal growth, while glucose homeostasis remains unperturbed [30, 31]. In contrast, Akt2-deficient mice show insulin resistance, mild glucose intolerance, and mild growth deficiency [32, 33]. According to one study, insulin-induced Akt2 activity, but not Akt1 activity, was significantly decreased in the livers of obese insulin-resistant rats as compared with that in the livers of lean rats [34]. This finding suggests that Akt 2 is an important signaling molecule in the regulation of metabolism by insulin signaling in the liver. Activated Akt is released from the plasma membrane, and is known to be involved in several cellular functions, such as glycogen synthesis, gluconeogenesis, lipogenesis, and protein synthesis in the liver [35] (Fig. 1). Glycogen synthase kinase-3 (GSK3) β is reported to play an important role in the regulation of insulin-induced glycogen synthesis [36, 37]. Activation of Akt by insulin phosphorylates, and thereby inhibits, GSK3β. Inactivation of GSK3β leads to dephosphorylation of glycogen synthase (GS) and increased glycogen synthesis in the liver. In the absence of insulin, GSK3β phosphorylates GS, resulting in decreased glycogen production. Insulin also activates GS by stimulating compartmentalized activation of protein phosphatase 1 (PP1) in an Akt-GSK3β-independent manner [38, 39].

Fig. 1  Insulin receptor signaling cascades in the liver

Insulin plays a crucial role in the regulation of glycogen synthesis (glycogenesis), gluconeogenesis (hepatic glucose production), and de novo fatty acid synthesis (lipogenesis) in the liver through the mediation of the insulin receptor, IRSs, and their downstream pathways in the liver.

Forkhead transcription factor (FoxO) 1 plays a key role in the regulation of gluconeogenesis by insulin [40-43]. FoxO1 is localized in the nucleus, where it directly binds to the promoters of gluconeogenic genes, such as those encoding glucose 6-phosphatase (G6Pase) and phosphoenol pyruvate carboxykinase (PEPCK), activating glucose production [44, 45]. Insulin stimulates phosphorylation of the Thr-24, Ser-256 and Ser-319 residues of FoxO1 by Akt [46-48]. Phosphorylated FoxO1 is translocated out of the nucleus and then ubiquitinated and degraded, which results in downregulation of the gluconeogenic genes. In addition, FoxO1 binds to an insulin response element (IRE) containing the promoter region of the IRS-2 gene. FoxO1 and IRS-2 are regulated reciprocally, with FoxO1 increasing the expression of IRS-2, and IRS-2, which is activated by insulin, causing downregulation of FoxO1 expression, forming a negative feedback loop. In fact, transgenic mice constitutively expressing active FoxO1 in the liver show increased hepatic IRS-2 expression [43], while liver-specific FoxO-deficient mice exhibit reduced hepatic IRS-2 expression [42].

The transcription factor steroid regulatory elementbinding protein (SREBP)-1c is a major mediator of the actions of insulin on the expressions of lipogenesis-related genes in the liver [49]. In fact, SREBP1c mRNA expression is reported to be decreased in the liver of the rat model of streptozotocin (STZ)-induced diabetes, and to be almost completely restored by insulin treatment [50]. SREBP-1c is synthesized as a precursor in the membranes of the endoplasmic reticulum. The active form of SREBP-1c is translocated to the nucleus and binds to specific response elements on the promoters of its target genes [50]. Insulin regulates SREBP-1c expression levels through the PI3 kinase-PKCλ/ε pathway [51, 52], and liver-specific knockout of PKCλ has been shown to lead to a marked decrease in SREBP-1c expression [53].

Insulin promotes protein synthesis via activation of mammalian target of rapamycin (mTOR) [54]. Akt activated by insulin phosphorylates the S939 and T1462 residues of tuberous sclerosis protein (TSC) 2 in the TSC1/TSC2 complex, and in turn, the phosphorylated TSC1/TSC2 complex reduces the GTPase activity of Rheb, causing activation of mTORC1 [55, 56]. mTORC1 increases the phosphorylation of 4EBP1 and S6K1, which results in increased protein synthesis and cell proliferation via activation of eIF4E and S6 protein [26].

2. Insulin actions on glucose metabolism

The liver plays an important role in the regulation of glucose homeostasis. In the fasting state, the liver produces glucose by two different mechanisms, namely, glycogenolysis and gluconeogenesis, to maintain blood glucose concentrations within the normal range. Glucose is produced by glycogenolysis during relatively short-term fasting [3, 57]. However, between meals and especially during the night, when the stores of glycogen are usually depleted, gluconeogenesis plays a greater role in providing glucose to the body [58]; gluconeogenesis accounts for up to 90% of the endogenous glucose production after 40 hours of fasting [59].

PEPCK and G6Pase are the rate-limiting enzymes of gluconeogenesis. PEPCK catalyzes the conversion of oxaloacetic acid to phosphoenol pyruvate and G6Pase hydrolyzes glucose-6-phosphate to form a phosphate group and release glucose in the endoplasmic reticulum. Expression levels of PEPCK and G6Pase are regulated by FoxO1. FoxO1 binds to the consensus FoxO-binding sites (IRE) in the promoter regions of the G6Pase and PEPCK genes, activating the expressions of these genes [42-44]. In addition to direct regulation of the expressions of gluconeogenic genes by FoxO1, peroxisome proliferator-activated receptor-γ coactivator (PGC)1α, a transcription coactivator, is also a major regulator of the expressions of gluconeogenic genes [59, 60]. PGC1α directly interacts with FoxO1 in the liver [45]. Matsumoto et al. reported that PGC1α cannot induce gluconeogenesis in liver-specific FoxO1-deficient mice [61]. Thus, both FoxO1 and PGC-1 seem to cooperate to fully induce expression of the G6Pase and PEPCK genes in the liver. Akt activated by insulin phosphorylates FoxO1 at 3 conserved sites, inhibiting FoxO1-stimulated transcription and translocation of the transcription factor from the nucleus to the cytoplasm. Akt activated by insulin also promotes the dissociation of PGC1α from FoxO1. Insulin suppresses gluconeogenesis via inhibiting the expressions of the PEPCK and G6Pase genes [62].

Mouse models with liver-specific knockout of the molecules involved in insulin receptor signaling are good tools to address the role of insulin signaling in the regulation of glucose metabolism in vivo. LIRKO mice show severely impaired glucose tolerance and insulin resistance with hyperinsulinemia [6]. The extreme hyperinsulinemia in these mice is considered to be due both to increased insulin secretion and a concomitant decrease in insulin clearance. Hepatic glucose production (HGP) was not suppressed by insulin in these mice, which showed increased hepatic G6Pase and PEPCK expressions. These data suggest the critical role played by the insulin receptor in the maintenance of glucose homeostasis in the liver. Moreover, like the LIRKO mice, the liver-specific IRS-1/IRS-2 double-knockout (LIRS1/2DKO) mice previously generated by us and other groups also exhibited severely impaired glucose tolerance and insulin resistance with hyperinsulinemia [63, 64], and indeed, HGP was significantly higher in the LIRS1/2DKO mice; consistent with this finding, the hepatic G6Pase and PEPCK expression levels were also increased in these mice. Insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 and recruitment of the p85 adaptor subunit of PI3 kinase to IRS-1 or IRS-2 immunoprecipitates were not detectable in the livers of the LIRS1/2DKO mice. Insulin-stimulated activation of PI3K associated with IRS-1, IRS-2, and tyrosinephosphorylated proteins, and insulin-stimulated phosphorylations of Akt, FoxO1, and GSK3β were also almost completely abrogated in these mice, suggesting that insulin receptor signaling is almost entirely mediated by IRS-1 and IRS-2 in the liver [62].

When adenoviruses expressing dominant-negative FoxO1 (DN-FoxO1) were introduced into the livers of the LIRS1/2DKO mice, the blood glucose and serum insulin levels before and after glucose loading in an oral glucose tolerance test (OGTT) were slightly, but significantly decreased, suggesting that FoxO1 indeed acts downstream of IRS-1 and IRS-2 and mediates insulin-induced regulation of glucose homeostasis. In fact, mice with liver-specific inactivation of FoxO1 showed lower blood glucose levels and increased insulin sensitivity; HGP and glucose levels in response to pyruvate administration were lower, and G6Pase and PEPCK expression levels were also decreased in these mice. In contrast, transgenic mice constitutively expressing active FoxO1 in the liver showed impaired glucose tolerance and insulin resistance with hyperinsulinemia [43]; the hepatic G6Pase and PEPCK expression levels were increased in these mice [62].

Mice systemically lacking Akt2 exhibit insulin resistance and mild diabetes, due at least in part to increased HGP [32]; the PEPCK expression levels were increased in these mice. Liver-specific Akt2-deficient mice with leptin deficiency (Lep^ob/ob) also showed increased plasma glucose and insulin levels [65]. Increased HGP was found in a hyperinsulinemic-euglycemic clamp study performed in human patients carrying a mutation in the kinase domain of Akt2 [66]. Taken together, these data are consistent with the notion that the IR-IRS-1/IRS-2-Akt2-FoxO1 pathway plays an important role in the regulating glucose homeostasis in the liver [62].

Although HGP is dominantly controlled by the direct actions of insulin on the liver, regulation of HGP by indirect effects of insulin in the liver has also been reported; restoration of insulin receptor expression in the livers of the LIRKO mice could not completely suppress HGP [67, 68]. Central administration of insulin has been demonstrated to inhibit HGP via activation of the K_ATP channel and consequently regulation of autonomic outflow to the liver [69-71]. Hepatic interleukin (IL)-6 and signal transducer and activator of transcription (STAT) 3 regulate, at least in part, HGP via hypothalamic insulin signaling [72].

3. Insulin actions on lipid metabolism

Increased blood glucose after a meal is taken up by the liver via glucose transporter type 2 (GLUT2), which is activated in an insulin signaling-independent manner. Once taken up by the liver, glucose is phosphorylated to G6P by glucokinase (GK), the expression of which is induced by insulin. Coincidentally, insulin inhibits the activity of G6Pase by the mechanism mentioned above. The final G6P concentrations are determined by the balance between the G6Pase and GK activities [39]. Insulin also activates several other enzymes, including GS, and increases glycogen synthesis. Glycogen is considered as the principal storage form of glucose and the liver shows the highest glycogen content [73]. However, as glycogen can only accumulate up to 5% of the liver mass, further synthesis is suppressed. When the liver is saturated with glycogen, glucose enters the glycolytic pathway and provides carbons for de novo lipogenesis. SREBP1c activated by insulin stimulates the transcription of genes involved in de novo lipogenesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) [74]. ACC converts acetyl-CoA to malonyl-CoA, which is not only a substrate for FAS, but also inhibits the activity of carnitine palmitoyl transferase (CPT)-1, preventing fatty acid transport into the mitochondria. FAS catalyzes the conversion of malonyl-CoA into long-chain saturated fatty acids. Insulin also stimulates FAS expression levels via the PI3 kinase pathway [1, 75]. Synthesis of saturated fatty acids is catalyzed by long-chain acyl-CoA synthetase (ACSL), and the synthesized fatty acids are elongated by an elongase (ELOVL6) and desaturated by stearoyl-CoA desaturase (SCD) [76]. Finally, triglycerides are formed in a condensation reaction between glycerol and fatty acids, catalyzed by the enzymes mitochondrial glycerol-3phosphate-acyltransferase (mtGATP) and diacylglycerol-acyltransferase (DGAT) [77]. Taken together, insulin promotes lipogenesis in the liver under physiological conditions. In fact, the triglyceride and free fatty acid contents were found to be significantly decreased in the livers of the LIRKO mice [6]. The expression levels of SREBP1c and GK were significantly decreased in the livers of the LIRS1/2DKO mice [63]. Liver-specific Akt2-deficient mice with leptin deficiency (Lep^ob/ob) also exhibited reduced hepatic triglyceride contents and serum triglyceride levels [65]. Consistent with these changes, the hepatic expression levels of SREBP1c, ACC and FAS were also significantly decreased in these mice.

4. Hepatic insulin actions under the fasting and feeding conditions

The liver plays an important role in maintaining the blood glucose levels within the normal range: while it ensures a sufficient supply of glucose in the fasting state, it stores the ingested carbohydrate as glycogen and synthesizes lipids in the fed state, although this dual function has not been fully explained by insulin signaling alone.

To investigate the role of IRS-1 and IRS-2 in the fasting and fed states, we generated LIRS-1KO and LIRS-2KO mice [63]. The glucose-lowering effect of insulin was intact in the LIRS-1KO mice, whereas it was significantly impaired under the fasting condition in the LIRS-2KO mice. Under the fed condition, the LIRS-2KO mice did not exhibit insulin resistance, while the LIRS-1KO mice showed insulin resistance. Thus, LIRS-1KO mice exhibited hepatic insulin resistance under the fed condition, but not under the fasting condition, while the LIRS-2KO mice exhibited hepatic insulin resistance under the fasting condition, but not under the fed condition. Indeed, the expression levels of PEPCK and G6Pase showed no significant differences between the two mouse models under the fasting condition, while suppression of the PEPCK and G6Pase expressions under the fed condition was significantly impaired in the LIRS-1KO mice. In contrast, although the expression levels of PEPCK and G6Pase under the fasting condition were significantly higher in the LIRS-2KO than in the LIRS-1KO mice, suppression of PEPCK and G6Pase expressions under the fed condition was similar between the control and LIRS-2KO mice. These data suggest that while the lack of IRS-1 affects insulin signaling under the fed condition, lack of IRS-2 affects insulin signaling under the fasting condition.

What is the implication of these differences observed between the LIRS-1KO and LIRS-2KO mice? The IRS-1 mRNA and protein expression levels remained unchanged at 6 hours after refeeding following 24 hours’ fasting, resulting in a 5-fold increase of the IRS-1-associated PI3K activity under the fed condition. In contrast, the IRS-2 mRNA and protein expression levels were significantly decreased after refeeding, resulting in the absence of any increase of the IRS-2-associated PI3K activity even under the fed condition. Moreover, the mRNA expression levels of IRS-1 were modestly upregulated during fasting and remained constant after refeeding, whereas the mRNA expression levels of IRS-2 increased markedly during the second half of the 24 hours fasting and fell immediately after refeeding. Moreover, the IRS-2 protein expression levels were upregulated during fasting and downregulated within an hour after refeeding. In contrast, the IRS-1 protein expression levels remained constant during fasting and after refeeding.

After feeding, the increased insulin release causes inactivation of FoxO1, and downregulation of IRS-2, but not IRS-1. Thus, the IRS-2-associated PI3 kinase activity remained high even during fasting and reached its peak immediately after refeeding because of insulin stimulation after refeeding, decreasing rapidly thereafter because of the downregulation of IRS-2 itself. In contrast, the PI3 kinase activity associated with IRS-1 began to increase a few hours after refeeding, steadily reaching its peak thereafter. These data suggest that IRS-2 mainly acts in the fasting state and immediately after refeeding, while IRS-1 takes the lead role thereafter. Based on these findings, we propose the concept of a functional relay between IRS-1 and IRS-2 in hepatic insulin signaling during fasting and after refeeding. IRS-2 mainly functions in the fasting state and immediately after refeeding, and IRS-1 primarily acts thereafter in the fed state. This also suggests that IRS-2 may be the main contributor to regulation of gluconeogenesis via the mediation of PEPCK and G6Pase, while IRS-1 may predominantly regulate lipogenesis by stimulating the expression of SREBP1c. In addition, in the OGTT conducted after fasting, the blood glucose and serum insulin levels were not significantly different between the control and LIRS-1KO mice. In contrast, the blood glucose levels after glucose loading, as well as the serum insulin levels before and after glucose loading in the OGTT conducted after fasting were significantly elevated in the LIRS-2KO mice. These data suggest that sufficient expression of hepatic IRS-2 during fasting appears to be pivotal for normal glucose homeostasis. If IRS-2 protein is abundantly expressed during fasting, the elevated glucose levels after refeeding promptly decrease. Consistent with this concept, Kuroda and colleagues reported that pulsatile insulin stimulation, such as by refeeding, induced temporal differences in the regulation of glycogen synthesis and inhibition of gluconeogenesis through the Akt signaling pathway [78, 79].

5. Hepatic insulin resistance

It has been observed in hyperinsulinemic-euglycemic clamp studies that hepatic insulin resistance cannot fully inhibit HGP. At the molecular level, hepatic insulin resistance can be referred to as an impairment of insulin signal transduction [75]. Chronic systemic inflammation and elevated circulating FFA levels associated with obesity have been proposed as playing important roles in the pathogenesis of hepatic insulin resistance [80-82].

Chronic inflammation results in abnormal production of inflammatory cytokines, such as tumor necrosis factor (TNF)α, IL-6, and IL-1β. These cytokines activate c-Jun NH(2)-terminal kinase (JNK) and inhibitor of κB kinase (IKK) β, which results in degradation of the inhibitor of κB (IκBα) and activation of nuclear factor-κB (NFκB). Activation of NFκB promotes further inflammatory gene expressions [83, 84] and inhibits insulin signaling through serine phosphorylation of IRS-1 or other insulin signaling molecules, leading to hepatic insulin resistance [85, 86]. Furthermore, the proinflammatory cytokines upregulate the expression of the suppressor of cytokine signaling (SOCS)3 through activation of transcription (STAT)- and NFκB-mediated pathways [83]. SOCS3 can bind to IR and inhibit phosphorylation of IRS-1 and IRS-2 [87-89].

Elevated FFA levels also activate inflammatory signaling pathways directly through interaction with members of the Toll-like receptor (TLR) family, specifically TLR4, which is a family of cell surface receptors involved in key events triggered by the innate immune system [90]. Activation of TLR4 by FFAs stimulates the TGFβ-activated kinase (TAK)1/TAK1-binding protein (TAB)1 complex, which activates IKKβ to stimulate the downstream NFκB inflammatory pathways in the liver [91]. In addition, excess FFAs result in a high net intracellular diacylglycerol (DAG) content in the liver [92]. Increased DAG activates PKC, which phosphorylates the serine residues in the β-subunit of the insulin receptor, resulting in impairment of the insulin receptor interaction with signaling proteins downstream, including IRS-1 and IRS-2 [83, 93, 94].

6. Hepatic steatosis

Hepatic steatosis is characterized by excessive accumulation of triglycerides in the liver, which can lead to hepatic inflammation and fibrosis of various grades of severity, and eventually, hepatic cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma (HCC). These phenomena have recently come to be called metabolic dysfunction-associated steatotic liver disease (MASLD) [95]. MASLD has been reported as being strongly associated with insulin resistance, obesity, and type 2 diabetes [96].

Although various mechanisms are thought to be involved in the development of hepatic steatosis, increased de novo lipogenesis is one of the most significant contributors to hepatic steatosis [97]. In fact, the expression levels of SREBP1c, which is one of the lipogenesis-related genes and a major mediator of insulin actions, was reported to be increased in Lep^ob/ob mice with fatty liver [98]. Absence of SREBP1c was associated with a reduced hepatic triglyceride content and fatty liver in Lep^ob/ob mice [99], while overexpression of SREBP1c was associated with an increase in the triglyceride content of the liver [100]. Consistent with these data obtained from animal experiments, the livers of obese patients were found to show higher expression levels of SREBP-1c as compared with those of control subjects, with a concomitant increase in the expression levels of FAS [101]. These data suggest that SREBP1c may play a crucial role in the development of fatty liver in patients with obesity. Since insulin can upregulate the expression levels of SREBP1c, as described above, the hyperinsulinemia seen in obesity may promote increased expression of SREBP1c, which leads to hepatic steatosis.

In addition to the SREBP1c expression levels, peroxisome proliferator-activated receptor (PPAR)γ expression levels were also reported to be markedly elevated in Lep^ob/ob and high fat (HF) diet-fed mice [102, 103], although PPARγ is predominantly expressed in the adipose tissues, and only to a lesser extent in the livers of normal mice [104]. Lep^ob/ob mice with liver-specific disruption of PPARγ exhibited improvement in fatty liver [105], while hepatic overexpression of PPARγ induced hepatic steatosis in PPARα-deficient mice [106]. Consistent with the data from animal experiments, hepatic PPARγ mRNA expression levels were reported to be significantly increased in obese MASLD patients with either steatosis or MASH [101]. These data suggest that PPARγ might also contribute to the regulation of lipid synthesis, promoting the development of liver steatosis. PPARγ expression levels are downregulated in fasting mice and mice with STZ-induced insulin-deficient diabetes [107]. Moreover, PPARγ expression has also been shown to be upregulated by insulin in vitro [108]. Thus, insulin seems to directly regulate the expression levels of PPARγ. On the other hand, recently, it was reported that Wnt-β-catenin signaling suppressed the expression levels of PPARγ [109]. Wnt-β-catenin signaling has been reported as playing a crucial role in the regulation of hepatic metabolism [110, 111]. However, the precise mechanism(s) of regulation of PPARγ expression in the liver remains unclear.

7. Selective insulin resistance in the liver

Under physiological conditions, insulin receptor signaling pathways in the liver act to suppress gluconeogenesis and promote lipogenesis, as described above. In fact, LIRKO, LIRS-1/2DKO and liver-specific Akt2-KO mice, in which insulin receptor signaling is completely abolished, show both increased gluconeogenesis and decreased lipogenesis. In humans, subjects with insulin receptor mutations show severe insulin resistance and hyperglycemia, but normal liver fat accumulation [112, 113]. Even more surprisingly, in humans with type 2 diabetes and obesity, hyperglycemia and hepatic steatosis often coexist. How does ‘hyperglycemia,’ which is a result of impaired insulin actions on glucose metabolism, coexist with ‘steatosis,’ which is a result of exaggerated insulin actions on the lipid metabolism in the liver in individuals with type 2 diabetes? This question has been asked by many investigators, including Brown and Goldstein [14], who proposed the concept of selective insulin resistance, which is a pathogenic paradox that could underlie the association between type 2 diabetes and obesity. According to their hypothesis, the PEPCK pathway is resistant to the actions of insulin, leading to hyperglycemia via upregulation of gluconeogenesis, while upregulation of SREBP1c through the augmented actions of insulin on lipogenesis results in steatosis and hypertriglyceridemia. As increased hepatic de novo lipogenesis in obese people with MASLD has been reported to be inversely correlated with hepatic and whole-body insulin sensitivity and directly correlated with the plasma insulin concentrations [114], it is possible that enhanced hepatic insulin signaling resulting from hyperinsulinemia in cases of MASLD might directly promote hepatic de novo lipogenesis. We previously identified that hepatic zonation of IRS-1 plays a crucial role in selective insulin resistance [115]. It has been demonstrated that the hepatic periportal (PP) zone is the primary site of gluconeogenesis, whereas the hepatic perivenous (PV) zone is the primary site of lipogenesis [116]. In mice on a HF diet, IRS-2 expression was significantly decreased in both the zones, whereas IRS-1 expression remained intact or even increased in the PV zone. This resulted in impaired insulin signaling and hyperglycemia in the PP zone, but enhanced insulin signaling and hepatic steatosis in the PV zone [62]. Moreover, in people with MASLD, IRS-2 expression was decreased, whereas the levels of the key enzymes involved in gluconeogenesis were increased. These changes in the expressions of IRS-2 and gluconeogenic enzymes exhibited robust inverse correlations. Conversely, FAS expression did not decrease in cases of MASLD despite the downregulation of IRS-2; rather, it showed a strong correlation with the IRS-1 expression [117]. These findings suggest that the distribution and alterations of IRS-1 and IRS-2 expressions play crucial roles in the development of selective insulin resistance in patients with obesity and type 2 diabetes [115].

8. Conclusion

Numerous studies have been conducted to identify the various causes of NAFLD and the mechanisms involved in its development. Recognition of the significant role of metabolic dysfunction, including insulin resistance, in the development of this condition prompted a shift in the terminology from NAFLD to MASLD. Recognizing MASLD as a hepatic manifestation of systemic insulin resistance may enhance the accuracy of diagnosis and the understanding of fatty liver disease, offering advantages in fundamental research, clinical care, and public health efforts. A better understanding of the insulin signaling cascades in the liver is essential for developing therapeutic strategies for obesity and type 2 diabetes.

Disclosure

The authors have nothing to disclose.

References

• 1   Bechmann  LP,  Hannivoort  RA,  Gerken  G,  Hotamisligil  GS,  Trauner  M, et al. (2012) The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 56: 952–964.
• 2   Nordlie  RC,  Foster  JD,  Lange  AJ (1999) Regulation of glucose production by the liver. Annu Rev Nutr 19: 379–406.
• 3   Weickert  MO,  Pfeiffer  AF (2006) Signalling mechanisms linking hepatic glucose and lipid metabolism. Diabetologia 49: 1732–1741.
• 4   Di Guglielmo  GM,  Drake  PG,  Baass  PC,  Authier  F,  Posner  BI, et al. (1998) Insulin receptor internalization and signalling. Mol Cell Biochem 182: 59–63.
• 5   Valera Mora  ME,  Scarfone  A,  Calvani  M,  Greco  AV,  Mingrone  G (2003) Insulin clearance in obesity. J Am Coll Nutr 22: 487–493.
• 6   Michael  MD,  Kulkarni  RN,  Postic  C,  Previs  SF,  Shulman  GI, et al. (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6: 87–97.
• 7   Taniguchi  CM,  Emanuelli  B,  Kahn  CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7: 85–96.
• 8   Fritsche  L,  Weigert  C,  Haring  HU,  Lehmann  R (2008) How insulin receptor substrate proteins regulate the metabolic capacity of the liver-implications for health and disease. Curr Med Chem 15: 1316–1329.
• 9   Sun  XJ,  Wang  LM,  Zhang  Y,  Yenush  L,  Myers MG  Jr, et al. (1995) Role of IRS-2 in insulin and cytokine signalling. Nature 377: 173–177.
• 10   Sun  XJ,  Rothenberg  P,  Kahn  CR,  Backer  JM,  Araki  E, et al. (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352: 73–77.
• 11   Horie  Y,  Suzuki  A,  Kataoka  E,  Sasaki  T,  Hamada  K, et al. (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113: 1774–1783.
• 12   Silverman  JF,  Pories  WJ,  Caro  JF (1989) Liver pathology in diabetes mellitus and morbid obesity: clinical, pathological, and biochemical considerations. Pathol Annu 24 Pt 1: 275–302.
• 13   Wanless  IR,  Lentz  JS (1990) Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12: 1106–1110.
• 14   Brown  MS,  Goldstein  JL (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 7: 95–96.
• 15   Patti  ME,  Kahn  CR (1998) The insulin receptor-a critical link in glucose homeostasis and insulin action. J Basic Clin Physiol Pharmacol 9: 89–109.
• 16   Sciacchitano  S,  Taylor  SI (1997) Cloning, tissue expression, and chromosomal localization of the mouse IRS-3 gene. Endocrinology 138: 4931–4940.
• 17   Liu  SC,  Wang  Q,  Lienhard  GE,  Keller  SR (1999) Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. J Biol Chem 274: 18093–18099.
• 18   Fantin  VR,  Lavan  BE,  Wang  Q,  Jenkins  NA,  Gilbert  DJ, et al. (1999) Cloning, tissue expression, and chromosomal location of the mouse insulin receptor substrate 4 gene. Endocrinology 140: 1329–1337.
• 19   Cai  D,  Dhe-Paganon  S,  Melendez  PA,  Lee  J,  Shoelson  SE (2003) Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem 278: 25323–25330.
• 20   Saltiel  AR,  Kahn  C (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: 799–806.
• 21   Nandi  A,  Kitamura  Y,  Kahn  CR,  Accili  D (2004) Mouse models of insulin resistance. Physiol Rev 84: 623–647.
• 22   Thirone  AC,  Huang  C,  Klip  A (2006) Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab 17: 72–78.
• 23   Ito  Y,  Vogt  PK,  Hart  JR (2017) Domain analysis reveals striking functional differences between the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85α and p85β. Oncotarget 8: 55863–55876.
• 24   Hay  N (2011) Akt isoforms and glucose homeostasis—the leptin connection. Trends Endocrinol Metab 22: 66–73.
• 25   Altomare  DA,  Guo  K,  Cheng  JQ,  Sonoda  G,  Walsh  K, et al. (1995) Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene 11: 1055–1060.
• 26   Hales  EC,  Taub  JW,  Matherly  LH (2014) New insights into Notch1 regulation of the PI3K-AKT-mTOR1 signaling axis: targeted therapy of γ-secretase inhibitor resistant T-cell acute lymphoblastic leukemia. Cell Signal 26: 149–161.
• 27   Altomare  DA,  Lyons  GE,  Mitsuuchi  Y,  Cheng  JQ,  Testa  JR (1998) Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin. Oncogene 16: 2407–2411.
• 28   Brodbeck  D,  Cron  P,  Hemmings  BA (1999) A human protein kinase Bγ with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem 274: 9133–9136.
• 29   Nakatani  K,  Sakaue  H,  Thompson  DA,  Weigel  RJ,  Roth  RA (1999) Identification of a human Akt3 (protein kinase B γ) which contains the regulatory serine phosphorylation site. Biochem Biophys Res Commun 257: 906–910.
• 30   Chen  WS,  Xu  PZ,  Gottlob  K,  Chen  ML,  Sokol  K, et al. (2001) Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 15: 2203–2208.
• 31   Cho  H,  Thorvaldsen  JL,  Chu  Q,  Feng  F,  Birnbaum  MJ (2001) Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276: 38349–38352.
• 32   Cho  H,  Mu  J,  Kim  JK,  Thorvaldsen  JL,  Chu  Q, et al. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). Science 292: 1728–1731.
• 33   Garofalo  RS,  Orena  SJ,  Rafidi  K,  Torchia  AJ,  Stock  JL, et al. (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ. J Clin Invest 112: 197–208.
• 34   Kim  YB,  Peroni  OD,  Franke  TF,  Kahn  BB (2000) Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats. Diabetes 49: 847–856.
• 35   Kadowaki  T,  Ueki  K,  Yamauchi  T,  Kubota  N (2012) SnapShot: insulin signaling pathways. Cell 148: 624, 624.e1.
• 36   Cross  DA,  Alessi  DR,  Cohen  P,  Andjelkovich  M,  Hemmings  BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785–789.
• 37   Lawrence JC  Jr,  Roach  PJ (1997) New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 46: 541–547.
• 38   Newgard  CB,  Brady  MJ,  O’Doherty  RM,  Saltiel  AR (2000) Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1. Diabetes 49: 1967–1977.
• 39   Postic  C,  Dentin  R,  Girard  J (2004) Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab 30: 398–408.
• 40   Nakae  J,  Biggs WH  3rd,  Kitamura  T,  Cavenee  WK,  Wright  CV, et al. (2002) Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 32: 245–253.
• 41   Qu  S,  Altomonte  J,  Perdomo  G,  He  J,  Fan  Y, et al. (2006) Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology 147: 5641–5652.
• 42   Matsumoto  M,  Han  S,  Kitamura  T,  Accili  D (2006) Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 116: 2464–2472.
• 43   Zhang  W,  Patil  S,  Chauhan  B,  Guo  S,  Powell  DR, et al. (2006) FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281: 10105–10117.
• 44   Ayala  JE,  Streeper  RS,  Desgrosellier  JS,  Durham  SK,  Suwanichkul  A, et al. (1999) Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. Diabetes 48: 1885–1889.
• 45   Puigserver  P,  Rhee  J,  Donovan  J,  Walkey  CJ,  Yoon  JC, et al. (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction. Nature 423: 550–555.
• 46   Brunet  A,  Bonni  A,  Zigmond  MJ,  Lin  MZ,  Juo  P, et al. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.
• 47   Kops  GJ,  de Ruiter  ND,  De Vries-Smits  AM,  Powell  DR,  Bos  JL, et al. (1999) Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398: 630–634.
• 48   Guo  S,  Rena  G,  Cichy  S,  He  X,  Cohen  P, et al. (1999) Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem 274: 17184–17192.
• 49   Shimomura  I,  Bashmakov  Y,  Ikemoto  S,  Horton  JD,  Brown  MS, et al. (1999) Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci U S A 96: 13656–13661.
• 50   Ferre  P,  Foufelle  F (2007) SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 68: 72–82.
• 51   Farese  RV,  Sajan  MP,  Standaert  ML (2005) Atypical protein kinase C in insulin action and insulin resistance. Biochem Soc Trans 33: 350–353.
• 52   Taniguchi  CM,  Kondo  T,  Sajan  M,  Luo  J,  Bronson  R, et al. (2006) Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab 3: 343–353.
• 53   Matsumoto  M,  Ogawa  W,  Akimoto  K,  Inoue  H,  Miyake  K, et al. (2003) PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. J Clin Invest 112: 935–944.
• 54   Laplante  M,  Sabatini  DM (2012) mTOR signaling in growth control and disease. Cell 149: 274–293.
• 55   Inoki  K,  Li  Y,  Zhu  T,  Wu  J,  Guan  KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4: 648–657.
• 56   Manning  BD,  Tee  AR,  Logsdon  MN,  Blenis  J,  Cantley  LC (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10: 151–162.
• 57   Gastaldelli  A,  Toschi  E,  Pettiti  M,  Frascerra  S,  Quiñones-Galvan  A, et al. (2001) Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients. Diabetes 50: 1807–1812.
• 58   Soon  GST,  Torbenson  M (2023) The liver and glycogen: in sickness and in health. Int J Mol Sci 24: 6133.
• 59   Boden  G (2003) Effects of free fatty acids on gluconeogenesis and glycogenolysis. Life Sci 72: 977–988.
• 60   Yoon  JC,  Puigserver  P,  Chen  G,  Donovan  J,  Wu  Z, et al. (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413: 131–138.
• 61   Matsumoto  M,  Pocai  A,  Rossetti  L,  Depinho  RA,  Accili  D (2007) Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab 6: 208–216.
• 62   Kubota  T,  Kubota  N,  Kadowaki  T (2017) Imbalanced insulin actions in obesity and type 2 diabetes: key mouse models of insulin signaling pathway. Cell Metab 25: 797–810.
• 63   Kubota  N,  Kubota  T,  Itoh  S,  Kumagai  H,  Kozono  H, et al. (2008) Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab 8: 49–64.
• 64   Dong  XC,  Copps  KD,  Guo  S,  Li  Y,  Kollipara  R, et al. (2008) Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 8: 65–76.
• 65   Leavens  KF,  Easton  RM,  Shulman  GI,  Previs  SF,  Birnbaum  MJ (2009) Akt2 is required for hepatic lipid accumulation in models of insulin resistance. Cell Metab 10: 405–418.
• 66   George  S,  Rochford  JJ,  Wolfrum  C,  Gray  SL,  Schinner  S, et al. (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304: 1325–1328.
• 67   Okamoto  H,  Obici  S,  Accili  D,  Rossetti  L (2005) Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J Clin Invest 115: 1314–1322.
• 68   Girard  J (2006) Insulin’s effect on the liver: “direct or indirect?” continues to be the question. J Clin Invest 116: 302–304.
• 69   Obici  S,  Zhang  BB,  Karkanias  G,  Rossetti  L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8: 1376–1382.
• 70   Pocai  A,  Lam  TK,  Gutierrez-Juarez  R,  Obici  S,  Schwartz  GJ, et al. (2005) Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434: 1026–1031.
• 71   Buettner  C,  Camacho  RC (2008) Hypothalamic control of hepatic glucose production and its potential role in insulin resistance. Endocrinol Metab Clin North Am 37: 825–840.
• 72   Inoue  H,  Ogawa  W,  Asakawa  A,  Okamoto  Y,  Nishizawa  A, et al. (2006) Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab 3: 267–275.
• 73   Taylor  R,  Magnusson  I,  Rothman  DL,  Cline  GW,  Caumo  A, et al. (1996) Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J Clin Invest 97: 126–132.
• 74   Foretz  M,  Guichard  C,  Ferre  P,  Foufelle  F (1999) Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci U S A 96: 12737–12742.
• 75   Sul  HS,  Latasa  MJ,  Moon  Y,  Kim  KH (2000) Regulation of the fatty acid synthase promoter by insulin. J Nutr 130: 315S–320S.
• 76   Nagle  CA,  Klett  EL,  Coleman  RA (2009) Hepatic triacylglycerol accumulation and insulin resistance. J Lipid Res 50 Suppl: S74–S79.
• 77   Coleman  RA,  Lee  DP (2004) Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 43: 134–176.
• 78   Kubota  H,  Noguchi  R,  Toyoshima  Y,  Ozaki  Y,  Uda  S, et al. (2012) Temporal coding of insulin action through multiplexing of the AKT pathway. Mol Cell 46: 820–832.
• 79   Noguchi  R,  Kubota  H,  Yugi  K,  Toyoshima  Y,  Komori  Y, et al. (2013) The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns. Mol Syst Biol 9: 664.
• 80   de Luca  C,  Olefsky  JM (2008) Inflammation and insulin resistance. FEBS Lett 582: 97–105.
• 81   Ginsberg  HN,  Zhang  YL,  Hernandez-Ono  A (2005) Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res 36: 232–240.
• 82   Olefsky  JM,  Glass  CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72: 219–246.
• 83   Nguyen  MT,  Favelyukis  S,  Nguyen  AK,  Reichart  D,  Scott  PA, et al. (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282: 35279–35292.
• 84   Aguirre  V,  Uchida  T,  Yenush  L,  Davis  R,  White  MF (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 275: 9047–9054.
• 85   Hotamisligil  GS (2006) Inflammation and metabolic disorders. Nature 444: 860–867.
• 86   Torisu  T,  Sato  N,  Yoshiga  D,  Kobayashi  T,  Yoshioka  T, et al. (2007) The dual function of hepatic SOCS3 in insulin resistance in vivo. Genes Cells 12: 143–154.
• 87   Emanuelli  B,  Peraldi  P,  Filloux  C,  Sawka-Verhelle  D,  Hilton  D, et al. (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275: 15985–15991.
• 88   Senn  JJ,  Klover  PJ,  Nowak  IA,  Zimmers  TA,  Koniaris  LG, et al. (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278: 13740–13746.
• 89   Ueki  K,  Kondo  T,  Tseng  YH,  Kahn  CR (2004) Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A 101: 10422–10427.
• 90   Schaeffler  A,  Gross  P,  Buettner  R,  Bollheimer  C,  Buechler  C, et al. (2009) Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology 126: 233–245.
• 91   Glass  CK,  Olefsky  JM (2012) Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab 15: 635–645.
• 92   Jornayvaz  FR,  Shulman  GI (2012) Diacylglycerol activation of protein kinase Cε and hepatic insulin resistance. Cell Metab 15: 574–584.
• 93   Samuel  VT,  Liu  ZX,  Wang  A,  Beddow  SA,  Geisler  JG, et al. (2007) Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 117: 739–745.
• 94   Zhang  D,  Liu  ZX,  Choi  CS,  Tian  L,  Kibbey  R, et al. (2007) Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci U S A 104: 17075–17080.
• 95   Rinella  ME,  Lazarus  JV,  Ratziu  V,  Francque  SM,  Sanyal  AJ, et al. (2023) A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 79: 1542–1556.
• 96   Tokushige  K (2024) New concept in fatty liver diseases. Hepatol Res 54: 125–130.
• 97   Pettinelli  P,  Obregon  AM,  Videla  LA (2011) Molecular mechanisms of steatosis in nonalcoholic fatty liver disease. Nutr Hosp 26: 441–450.
• 98   Shimomura  I,  Bashmakov  Y,  Horton  JD (1999) Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 274: 30028–30032.
• 99   Yahagi  N,  Shimano  H,  Hasty  AH,  Matsuzaka  T,  Ide  T, et al. (2002) Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem 277: 19353–19357.
• 100   Shimano  H,  Horton  JD,  Shimomura  I,  Hammer  RE,  Brown  MS, et al. (1997) Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 99: 846–854.
• 101   Pettinelli  P,  Videla  LA (2011) Up-regulation of PPAR-γ mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab 96: 1424–1430.
• 102   Rahimian  R,  Masih-Khan  E,  Lo  M,  van Breemen  C,  McManus  BM, et al. (2001) Hepatic over-expression of peroxisome proliferator activated receptor γ2 in the ob/ob mouse model of non-insulin dependent diabetes mellitus. Mol Cell Biochem 224: 29–37.
• 103   Inoue  M,  Ohtake  T,  Motomura  W,  Takahashi  N,  Hosoki  Y, et al. (2005) Increased expression of PPARγ in high fat diet-induced liver steatosis in mice. Biochem Biophys Res Commun 336: 215–222.
• 104   Braissant  O,  Foufelle  F,  Scotto  C,  Dauca  M,  Wahli  W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137: 354–366.
• 105   Matsusue  K,  Haluzik  M,  Lambert  G,  Yim  SH,  Gavrilova  O, et al. (2003) Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 111: 737–747.
• 106   Yu  S,  Matsusue  K,  Kashireddy  P,  Cao  WQ,  Yeldandi  V, et al. (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression. J Biol Chem 278: 498–505.
• 107   Vidal-Puig  A,  Jimenez-Linan  M,  Lowell  BB,  Hamann  A,  Hu  E, et al. (1996) Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J Clin Invest 97: 2553–2561.
• 108   Werman  A,  Hollenberg  A,  Solanes  G,  Bjorbaek  C,  Vidal-Puig  AJ, et al. (1997) Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor γ (PPARγ). Differential activity of PPARγ1 and -2 isoforms and influence of insulin. J Biol Chem 272: 20230–20235.
• 109   Hoshiba  T,  Kawazoe  N,  Chen  G (2011) Mechanism of regulation of PPARG expression of mesenchymal stem cells by osteogenesis-mimicking extracellular matrices. Biosci Biotechnol Biochem 75: 2099–2104.
• 110   Liu  H,  Fergusson  MM,  Wu  JJ,  Rovira  II,  Liu  J, et al. (2011) Wnt signaling regulates hepatic metabolism. Sci Signal 4: ra6.
• 111   Boj  SF,  van Es  JH,  Huch  M,  Li  VS,  Jose  A, et al. (2012) Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell 151: 1595–1607.
• 112   Musso  C,  Cochran  E,  Moran  SA,  Skarulis  MC,  Oral  EA, et al. (2004) Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 83: 209–222.
• 113   Semple  RK,  Sleigh  A,  Murgatroyd  PR,  Adams  CA,  Bluck  L, et al. (2009) Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest 119: 315–322.
• 114   Smith  GI,  Shankaran  M,  Yoshino  M,  Schweitzer  GG,  Chondronikola  M, et al. (2020) Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest 130: 1453–1460.
• 115   Kubota  N,  Kubota  T,  Kajiwara  E,  Iwamura  T,  Kumagai  H, et al. (2016) Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity. Nat Commun 7: 12977.
• 116   Sakurai  Y,  Kubota  N,  Yamauchi  T,  Kadowaki  T (2021) Role of insulin resistance in MAFLD. Int J Mol Sci 22: 4156.
• 117   Honma  M,  Sawada  S,  Ueno  Y,  Murakami  K,  Yamada  T, et al. (2018) Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. Int J Obes (Lond) 42: 1544–1555.

Abbreviations

ACC

Acetyl-CoA carboxylase

ACSL

Long-chain acyl-CoA synthetase

Akt/PKB

Akt/protein kinase B

CPT

Carnitine palmitoyl transferase

DAG

Diacylglycerol

DGAT

Diacylglycerol acyltransferase

ELOVL6

Elongase of very long chain fatty acids 6

FoxO

Forkhead transcription factor

G6Pase

Glucose 6-phosphatase

GK

Glucokinase

GLUT2

Glucose transporter type 2

GS

Glycogen synthase

GSK3

Glycogen synthase kinase 3

HCC

Hepatocellular carcinoma

HF

High fat

HGP

Hepatic glucose production

IκBα

Inhibitor of κB

IKK

Inhibitor of κB kinase

IRE

Insulin response element

IRS

Insulin receptor substrate

JNK

c-Jun NH(2)-terminal kinase

MASLD

Metabolic dysfunction-associated steatotic liver disease

mtGATP

Mitochondrial glycerol-3-phosphate acyltransferase

NFκB

Nuclear factor-κB

OGTT

Oral glucose tolerance test

PDK1

3-phosphoinositide-dependent protein kinase 1

PEPCK

Phosphoenol pyruvate carboxykinase

PP

Periportal

PI3

Phosphoinositide 3

PV

Perivenous

PPAR

Peroxisome proliferator-activated receptor

PGC

Peroxisome proliferator-activated receptor-γ coactivator

PP1

Protein phosphatase 1

PTB

Phosphotyrosine-binding

SCD

Stearoyl-CoA desaturase

SH2

Src homology 2

SOCS

Suppressor of cytokine signaling

SREBP

Steroid regulatory element-binding protein

STAT

Signal transducer and activator of transcription

STZ

Streptozotocin

TAB

TAK1-binding protein

TAK

TGFβ-activated kinase

TLR

Toll-like receptor

TNF

Tumor necrosis factor

TSC

Tuberous sclerosis protein

VLDL

Very low-density lipoprotein