The role of bile acids in regulating glucose and lipid metabolism

Abstract

In recent years, bile acids (BAs) are increasingly being appreciated as signaling molecules beyond their involvement in bile formation and fat absorption. The farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) are two dominating receptors through which BAs modulate glucose and lipid metabolism. FXR is highly expressed in the intestine and liver. GPBAR1 is highly expressed in the intestine. The present study reviews the metabolism and regulation of BAs, especially the effects of BAs on glucose and lipid metabolism by acting on FXR in the liver and intestine, and GPBAR1 in the intestine. Furthermore, it explains that fibroblast growth factor 15/19 (FGF15/19), ceramide, and glucagon like peptide-1 (GLP-1) are all involved in the signaling pathways by which BAs regulate glucose and lipid metabolism. This article aims to provide an overview of the molecular mechanisms by which BAs regulate glucose and lipid metabolism, and promote further scientific and clinical research on BAs.

Introduction

Glucose and lipid metabolism disorders are the main clinical manifestations of obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) and can lead to cardiovascular and cerebrovascular diseases [1]. Over the past decades, bile acids (BAs) are considered only to dissolve cholesterol in the gallbladder and facilitate the emulsification and uptake of lipids in the gut [2]. However, BAs have been increasingly appreciated as signal molecules since they were reported to be the natural ligands of the farnesoid X receptor (FXR) in 1999 [3-5]. BAs signaling is a critical regulator of glucose and lipid metabolism, mainly through nuclear receptor FXR and cell surface-located G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) [6-9]. FXR and GPBAR1 are widely expressed in many tissues. In particular, FXR is substantially expressed in the liver, ileum, and colon. GPBAR1 is highly expressed in enteroendocrine cells, gallbladder, and bile duct [8]. This study focuses on the roles and molecular mechanisms of BAs in regulating glucose and lipid metabolism via hepatic and intestinal FXR and intestinal GPBAR1. It will serve as a foundation for future scientific and clinical research.

Metabolism of BAs

Synthesis of BAs

BAs, as amphipathic steroid molecules, are synthesized by hepatic cholesterol and excreted into bile as an essential component. The classical and alternative pathways are the two main pathways for synthesizing BAs. The classical pathway begins with modifying steroidal rings of cholesterol in the cytoplasm and endoplasmic reticulum (including hydroxylation, isomerization, reduction, and dehydroxylation), followed by oxidation of steroidal side chains in mitochondria and oxidative cleavage of side chains in peroxisomes. The oxidation of steroidal side chains initiates the alternate pathway, followed by the modification of steroidal rings and the oxidative cleavage of steroidal side chains [10]. The classical pathway favors cholic acid (CA) and chenodeoxycholic acid (CDCA) biosynthesis. The classic pathway is initiated by cytochrome P450 family 7 subfamily A member 1 (CYP7A1), the only rate-limiting enzyme, which also determines the amount of the BA synthesis. Cytochrome P450 family 8 subfamily B member 1 (CYP8B1)-another critical enzyme, controls the proportion of CA and CDCA products [11]. The alternative pathway is initiated by cytochrome P450 family 27 subfamily A member 1 (CYP27A1), which converts cholesterol into 27-hydroxycholesterol. Further, it undergoes hydroxylation of cytochrome P450 family 7 subfamily B member 1 (CYP7B1) followed by a series of enzymatic reactions and mainly synthesizes CDCA. Under normal human physiological conditions, less than 10% of total BAs come from the alternative pathway [12]. The contribution of rodent alternative pathways to BAs synthesis, on the other hand, is roughly the same as that of the classical pathways [10] (Fig. 1).

Fig. 1

Synthesis and circulation of bile acids. The conversion of cholesterol into bile acids in the liver involves the classic (CA and CDCA) and alternative (CDCA) pathway. The initial products of the two pathways are the primary bile acids (CA and CDCA in humans and CA, CDCA, UDCA, αMCA and βMCA in rodents). Primary bile acids are conjugated to either taurine or glycine, and then are excreted into the bile and stored in the gallbladder, followed by transport to the duodenum when necessary. In the colon, primary bile acids are changed into secondary bile acids (DCA, LCA, UDCA in humans and DCA, LCA, HCA, MDCA, ωMCA, HDCA in murine). Bile acids were reabsorbed into the portal vein from the terminal ileum and colon, and then taken in by the liver from the portal blood and re-secreted into bile, as is enterohepatic circulation.

CYP7A1, cytochrome P450 family 7 subfamily A member 1; CYP8B1, cytochrome P450 family 8 subfamily B member 1; CYP27A1, cytochrome P450 family 27 subfamily A member 1; CYP7B1, cytochrome P450 family 7 subfamily B member 1; CYP2C70, cytochrome P450 family 2 subfamily C member 70; CYP2A12, cytochrome P450 family 2 subfamily A member 12; CA, cholic acid; CDCA, chenodeoxycholic acid; UDCA, ursodeoxycholic acid; αMCA, α-Muricholic acid; βMCA, β-Muricholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; HCA, hyocholic acid; MDCA, murideoxycholic acid; ωMCA, ω-Muricholic acid; HDCA, hyodeoxycholic acid; BSH, bile acid salt hydrolysis enzyme; BSEP, bile salt export protein; NTCP, sodium taurocholate co-transporting polypeptide; ASBT, apical sodium dependent bile acid transporter; OSTα/β, organic solute transporter α/β; BAs, bile acids; T, taurine-conjugated species; G, glycine-conjugated species; TBA, taurine-conjugated bile acid; GBA, glycine-conjugated bile acid

According to their sources, BAs are divided into primary and secondary BAs. CA and CDCA are the primary BAs in humans. In rodents, cytochrome P450 family 2 subfamily C member 70 (CYP2C70) can hydroxylate CDCA at the 6β-position to form α muricholic acid (MCA) and ursodeoxycholic acid (UDCA) to form βMCA [13, 14]. Meanwhile, in rodent liver, cytochrome P450 family 2 subfamily A member 12 (CYP2A12) is responsible for BA 7α-rehydroxylation and metabolizes deoxycholic acid (DCA, derived from the intestine via enterohepatic circulation) to CA [14]. CYP2C70 and CYP2A12 make BA composition in rodents substantially different from that in humans. The primary BAs in rodents are CA, CDCA, UDCA, αMCA, and βMCA (among MCAs, βMCA is the central part). Primary conjugated BAs are first hydrolyzed into free BAs by bile acid salt hydrolysis enzyme (BSH) in the colon. Subsequently, in human differential isomerization produces UDCA; DCA and lithocholic acid (LCA), the secondary BAs, are generated by 7a-dehydroxylase. In rodents, hyocholic acid (HCA), murideoxycholic acid (MDCA), ωMCA, hyodeoxycholic acid (HDCA), DCA, and LCA are generated by 7a-dehydroxylase. Further, according to whether it binds to glycine or taurine, BAs can be categorized into conjugated BAs and un-conjugated BAs. Once synthesized, the primary BAs in the liver combine with glycine or taurine, and then are excreted into the bile, followed by transport to the duodenum when necessary. BAs mainly bind with glycine in humans. In contrast, they bind with taurine in rodents [15-17] (Fig. 1).

Circulation of BAs

BAs are secreted into bile canaliculi via the adenosine triphosphate (ATP)-dependent bile salt export pump (BSEP) after being synthesized in hepatocytes [18]. Subsequently, BAs with cholesterol, lecithin, potassium, sodium, and calcium form micelles stored in the gallbladder. Eating induces the gallbladder to contract and empty bile into the duodenum. BAs are highly reabsorbed into enterocytes by apical sodium-dependent bile acid transporter (ASBT) in the small intestine (mainly the distal ileum). BAs enter the portal vein [19] by organic solute transporter α/β (OSTα/β) on the basal side of intestinal epithelial cells. They return to the liver via the portal circulation, and are transported into hepatocytes by sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) on the hepatocyte membrane [20]. In the small and large intestines, un-conjugated BAs are passively diffused and reabsorbed; primary conjugated BAs are reabsorbed efficiently and actively in the distal ileum; all of them are transported into hepatocytes via the portal circulation, and subsequently released into the bile; this process is called enterohepatic circulation [18]. The human body has a bile acid pool with an average size of 2 g that circulates 10 times a day, and the liver and intestine can transport 20 g of BAs every 24 h. 95% of BAs are reused after enterohepatic circulation, and only approximately 5% of BAs are excreted with feces. About 0.6 g BAs are lost per day in humans, and require de novo synthesis in the liver, to maintain a constant bile acid pool [21] (Fig. 1).

Regulation of Bile Acid Metabolism

The BAs regulate their amount mainly by themselves. The body regulates the excessive accumulation of BAs in circulation in various ways. BAs mainly have a feedback inhibition on the expression of CYP7A1 in the liver and reduce their content by hepatic FXR-small heterodimer partner (SHP) and ileal FXR-fibroblast growth factor (FGF) 15/19 signal pathway [22]. In the liver, FXR is activated by BAs, and next induces the expression of the target gene Shp. SHP suppresses the expression of the gene Cyp7a1 and reduces the production of BAs by binding to liver receptor homolog-1 [23-25]. Apart from the local negative feedback effect in the liver, BAs also regulate the synthesis of hepatic BAs in remote negative feedback via the intestinal-hepatic pathway. BAs can activate FXR in the terminal ileum. FXR promotes the expression of the target gene Fgf 15, which is FGF19 in humans. FGF15/19 enters the liver via the portal system, where it binds to the FGF receptor 4/β-Klotho heterodimer complex, triggers the c-Jun N-terminal kinase 1/2 and extracellular signal-regulated kinase (ERK) 1/2 cascade reaction, and further suppresses the expression of CYP7A1 and the production of BAs [26] (Fig. 2).

Fig. 2

The self-regulation of bile acids metabolism. Bile acid synthesis is modulated by negative feedback pathway (hepatic FXR-SHP axis and ileal FXR-FGF15/19 axis). Furthermore, AMPK and SIRT1 regulate BAs amount by hepatic and intestinal FXR.

BAs, bile acids; FXR, farnesoid X receptor; FGF15/19, fibroblast growth factor 15/19; SHP, small heterodimer partner; LRH-1, liver receptor homolog-1; FGFR4, fibroblast growth factor receptor 4; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; CYP7A1, cytochrome P450 family 7 subfamily A member 1; AMPK, adenosine monophosphate activated protein kinase; SIRT1, sirtuin 1; HNF-1α, hepatocyte nuclear factor 1α; ASBT, apical sodium dependent bile acid transporter

Furthermore, by influencing hepatic and intestinal FXR, adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) regulate the amounts of BAs. The pharmacological activation of AMPK inhibited the transcriptional activity of FXR and prevented FXR coactivator recruitment to promoters of FXR-regulated genes in cultured human and murine hepatocytes and enterocytes. Metformin (an AMPK agonist) induced FXR phosphorylation, reduced FXR transcriptional activity, disrupted bile-acid balance, and aggravated liver damage in the mouse intrahepatic-cholestasis model [27]. SIRT1, an essential metabolic sensor in various tissues, is the most conserved mammalian oxidized nicotinamide adenine dinucleotide-dependent protein deacetylase. SIRT1 deacetylates the dimerization cofactor of hepatocyte nuclear factor 1a 2 (DCoH2), promotes the interaction between DCoH2 and hepatocyte nuclear factor 1a (HNF-1a), and induces HNF-1α binding to DNA, as shown in animal studies. In mice, intestinal epithelial cell SIRT1 knockout (SIRT1^ΔIE) reduced the expression of intestinal FXR by HNF-1a, further decreasing the expression of BAs transport gene Asbt and the reabsorption of ileal BAs. As a result, it reduced the amount of BAs reaching the liver by enterohepatic circulation, increased its biosynthesis as compensation, reduced its accumulation, and protected animals from liver damage caused by a high bile-acid diet. It suggests that SIRT1 (a key nutritional sensor) is involved in regulating ileal bile-acid absorption and maintaining systemic bile-acid homeostasis in mice by the HNF-1a-FXR-ASBT signal pathway [28] (Fig. 2).

BAs Affect Glucose and Lipid Metabolism by Hepatic FXR

FXR is a member of the nuclear receptor superfamily and is highly expressed in the liver and intestine, with BAs as its natural ligands. Un-conjugated BAs have a stronger ability to activate FXR than conjugated BAs. CDCA > DCA > LCA > CA is the order of activation intensity [29]. Tauro-alpha-muricholic acid (TαMCA), tauro-beta-muricholic acid (TβMCA), and UDCA have been discovered to have significant antagonistic effects on FXR in recent research [30]. After interacting with FXR, different BAs can regulate glucose and lipid metabolism via different metabolic pathways.

BAs reduce hepatic lipids by hepatic FXR

Hepatic FXR can be activated by CA, resulting in increased expression of the target gene Shp. SHP reduces hepatic lipid production by inhibiting the expression of transcription factor sterol regulatory element-binding protein 1c (SREBP-1c) and its downstream lipid synthesis genes [31]. In addition, decreases in hepatic lipids after FXR activation are due to FXR-dependent repression of stearoyl coenzyme A desaturase-1 (Scd-1), diglyceride acyltransferase 2, and phosphatidic acid phosphatase 1 expression, which is independent of SHP and SREBP-1c [32]. CDCA increases fatty acid oxidation by activating FXR and inducing the production of peroxisome proliferator-activated receptor alpha—the primary regulator of fatty acid metabolism [33]. Hence, hepatic FXR activation can cause lipid decomposition, reduce lipid synthesis, increase fatty acid oxidation, and lastly reduce hepatic lipid level [34].

BAs reduce hepatic glucose by hepatic FXR

SHP can interact with hepatocyte nuclear factor-4 alpha (HNF4α) and forkhead box protein O1 (FOXO1) after CA induces SHP expression through FXR, in addition to the above pathways. The interaction inhibits the promoter activity of HNF4α target genes like phosphoenolpyruvate carboxykinase, fructose 1,6-bis phosphatase, and FOXO1 target genes such as glucose-6-phosphatase, and further reduces hepatic gluconeogenesis [35].

BAs Affect Glucose and Lipid Metabolism by Inhibiting Intestinal FXR

Intestinal FXR-SHP/FGF15/19 signal pathway

After being fed a high-fat diet (HFD), Fxr^ΔIE mice showed lower obesity and insulin resistance than the wild-type mice, with a significant increase in the expression of intestinal fatty acid β-oxidation-related genes. The gut microbiota composition of the mice being given Tempol changed and TβMCA increased, leading to decreased intestinal FXR signal transduction, further decreased SHP and FGF15 (reaching the liver through enterohepatic circulation), and consequently increased CYP7A1 expression, compared with the control group [36]. Accordingly, hepatic cholesterol decreased, and obesity and insulin resistance improved [36]. Oral metformin has been found to alter gut microbiota, enhance tauro-ursodeoxycholic acid (TUDCA) levels, and inhibit the intestinal FXR signal pathway, hence improving metabolic diseases such as hyperglycemia [37]. Another study has shown a significant increase in hepatic CYP7B1 after HFD-fed hamsters were treated with antibiotics and their gut microbiota was eliminated. Furthermore, the CDCA synthesized through alternative pathways increased, intestinal TβMCA increased, and intestinal FXR-SHP/FGF19 signaling pathway was inhibited, leading to decreased levels of hepatic lipid synthesis related gene Srebp1c, fatty acid synthase, Scd-1, and acetyl CoA carboxylase. Consequently, hepatic lipid synthesis decreased, and overall glucose tolerance and fatty liver improved [38] (Fig. 3).

Fig. 3

Bile acids regulate glucolipid metabolism through intestinal FXR and GPBAR1. Bile acids activate or inhibit the intestinal FXR, further regulate the expression of FGF15/19, ceramide, GLP-1, NPC1L1, and affect glucolipid metabolism. Moreover, bile acids can activate the pathways of GPBAR1-GLP-1 in the intestine and GPBAR1-DiO2 in the WAT and BAT, and improve the glucose and lipid metabolism.

BAs, bile acids; TβMCA, tauro-beta-muricholic acid; TUDCA, tauro-ursodeoxycholic acid; Gly-MCA, glycine-β-muricholic acid; GUDCA, glyco-ursodeoxycholic acid; HCA, hyocholic acid; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; TCA, tauro-cholic acid; TLCA, tauro-lithocholic acid; FXR, farnesoid X receptor; GPBAR1, G protein-coupled bile acid receptor 1, also known as TGR5; SHP, small heterodimer partner; SREBF2, sterol regulatory element-binding factor 2; NPC1L1, NPC1-like intracellular cholesterol transporter; SMPD3, sphingomyelin phosphodiesterase 3; FFA, free fatty acids; SCFA, short-chain fatty acids; FFAR2, SCFA receptor 2; IP3, inositol tri-phosphate; ATP, adenosine triphosphate; GLP-1, glucagon-like peptide-1; cAMP, cyclic adenosine monophosphate; CREBP, cAMP response element‐binding protein; PC1, prohormone convertases subtilisin/kexin type 1; NFAT, nuclear factor of activated T cells; PC1/3, prohormone convertases 1/3; mTORC1, mechanistic target of rapamycin complex 1; G6PC, glucose-6-phsophatase catalytic; PCK, phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α; CYP7A1, cytochrome P450 family 7 subfamily A member 1; TC, total cholesterol; GS, glycogen synthase; SREBP-1c, sterol regulatory element-binding protein 1c; FA, fatty acid; PC, pyruvate carboxylase; WAT, white adipose tissue; BAT, brown adipose tissue; DIO2, deiodinase 2

Intestinal FXR-Ceramide signal pathway

Ceramide belongs to the sphingolipid family, which is composed of fatty acids and long-chain sphingosine bases. Increased ceramide levels in serum and tissues have been shown to cause insulin resistance, damage glucose tolerance, and eventually lead to diabetes or NAFLD in animal studies [39]. Sphingomyelin phosphodiesterase 3 (SMPD3), which participates in intestinal ceramide synthesis, was identified as an FXR target gene [40]. The plasma ceramide level decreased in Fxr^ΔIE mice, ameliorating metabolic diseases induced by a high-fat diet [41]. Fxr^ΔIE mice had significantly lower liver weight, liver/body weight ratio, and liver triglyceride content than wild-type mice after being fed on HFD. Obese mice administered with the antioxidant Tempol or antibiotics had lower intestinal lumen BSH activity, and higher TβMCA levels, further leading to reduced intestinal FXR activity, and lower ceramide levels in the intestine and blood. Decreased ceramide inhibits de novo synthesis of hepatic lipids through SREBP-1c [42] and enhances the browning of white adipose tissue (WAT) and the thermogenic capacity of brown adipose tissue (BAT) [43]. Glycine-β-muricholic acid (Gly-MCA), an intestinal FXR-specific inhibitor, can also improve obesity and glucose and lipid metabolism in mice [43]. In addition, the administration of glyco-ursodeoxycholic acid (GUDCA, a natural antagonist of intestinal FXR) mitigates atherosclerosis in ApoE^–/– mice by inhibiting an intestinal FXR/SMPD3 axis with decreasing circulating ceramide levels [40]. As per previous studies, CYP8B1 knockout mice exhibit lower CA and DCA levels and further lower FXR-Ceramide-SREBP-1c axis signal, resulting in attenuated hepatic lipid synthesis, and improved blood lipid disorder [44]. Reducing CA may be a potential target for improving blood lipid disorder and NAFLD [44] (Fig. 3).

Caffeic acid phenethyl ester can prevent HFD-fed rats from weight gain, reduce blood glucose and insulin levels in the fasting state, and treat type 2 diabetes [45]; however, these positive benefits are lost in Fxr^ΔIE mice. The mechanism is like that of Tempol. Caffeic acid phenethyl ester decreases ceramide levels in the intestine and blood via the BSH-TβMCA-FXR pathway, further reducing endoplasmic reticulum (ER) stress and ER-mitochondrial coupling and Ca²⁺ overload, lastly inhibiting the activities of acetyl CoA and pyruvate carboxylase (PC) in liver mitochondria and reducing hepatic gluconeogenesis [46]. This is termed as the FXR-Ceramide-PC pathway in this article (Fig. 3).

Intestinal FXR-glycolysis-GLP-1 signal pathway

Glucagon-like peptide-1 (GLP-1) is a multifunctional peptide hormone produced and secreted mostly by epithelial L cells of the intestinal mucosa. It can improve obesity and insulin resistance by stimulating insulin secretion after meals, inhibiting appetite, and promoting islet β cell proliferation [47]. GLP-1 is the product of the proglucagon peptide, encoded by the preproglucagon gene and processed and modified by prohormone convertases 1/3 (PC1/3) [47]. Hormones, nerves, nutritional stimulation, gut microbiota, and other factors influence its secretion [48]. According to Trabelsi et al., L cells expressed FXR. In mice, FXR knockout increased glucose-stimulated GLP-1 expression and secretion and improved glucose metabolism [49]. After the FXR activation, glycolysis weakened. It reduces the expression of transcription factor carbohydrate response element-binding protein (ChREBP) and decreases glucagon transcription and GLP-1 production in L cells [49]. Simultaneously, GLP-1 secretion is reduced by inhibiting intracellular ATP production [49] (Fig. 3).

Intestinal FXR-FFAR2-GLP1 signal pathway

Short-chain fatty acids (SCFA) produced by microbial fermentation, such as acetate, propionate, and butyrate, can be increased and energy homeostasis is improved by inulin-type fructans (ITF) [50, 51]. Studies have shown that when mice were fed with HFD and ITF, the serum GLP-1 level of Fxr^–/– mice was significantly higher than that of wild-type mice [52]. The colon short-chain fatty acid receptor 2 (SCFA receptor 2, Ffar2) gene was upregulated after Fxr knockout, and the downstream Gαq-Ca²⁺/inositol triphosphate (IP3) was activated, resulting in increased GLP-1 secretion stimulated by SCFA [52]. CA and its derivatives are absent in Cyp8b1^–/– mice, their intestinal fat absorption reduces, and the free fatty acids (FFA) reaching ileal L cells increase, resulting in increased GLP-1 secretion [53]. This process could be related to an increase in ileal TβMCA caused by the change of gut flora, FXR inhibition, and subsequent FFAR2-GLP1 pathway activation. FXR agonist GW4064 was given to STC-1 cells in vitro. FXR bound with cyclic adenosine monophosphate (cAMP) response element-binding protein (CREBP) caused inhibition of CREBP’s transcriptional activity, and finally GLP-1 secretion was reduced due to the reduction in the level of proprotein convertase subtilisin/kexin type 1 [54] (Fig. 3).

Intestinal FXR-SCFA-de novo lipogenesis signal pathway

Oral administration of intestinal FXR inhibitor Gly-MCA significantly reduces the ratio of firmicutes/bacteroidetes (F/B) in HFD-fed animals, lowering SCFA production (liver lipid synthesis raw material) and de novo lipid synthesis in the liver and improving metabolic syndromes such as obesity [55]. However, in Fxr^ΔIE mice, the above metabolic improvement effect disappears [55].

BAs Affect Glucose and Lipid Metabolism by Activating Intestinal FXR

Intestinal FXR-FGF15/19 signal pathway

Fang et al. showed that the expression of the intestinal Fgf15 gene was upregulated, BAT energy consumption increased, and WAT browned after administration of fexaramine (FEX), an intestinal-specific FXR agonist in HFD-fed mice [56]. Uncoupling protein 1 (Ucp1) gene expression was upregulated, while liver gluconeogenic genes like glucose-6-phosphatase catalytic, phosphoenolpyruvate carboxykinase and lipid synthesis genes like Srebp1c, fatty acid synthase, and Scd-1 gene expression was down-regulated [56]. Consequently, metabolic syndrome such as obesity and inflammation was improved [56]. FGF15 given intravenously was also demonstrated to activate ERK, then inhibit glycogen synthase kinase 3, activate hepatic glycogen synthase, and enhance hepatic glycogen production in mice [57]. FGF15 can also inactivate hepatic transcription factor CREB by dephosphorylation, inhibiting the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and downstream gluconeogenesis-related target gene, and thereby reducing the production of hepatic glucose [58] (Fig. 3).

Intestinal FXR-GPBAR1-GLP1 signal pathway

Glucose-induced plasma GLP-1 levels in Fxr^–/– or Gpbar1^–/– mice decreased by 40% compared with wild-type mice [59]. In Gpbar1^–/– mice, the expression of FXR was normal and the secretion of GLP-1 increased significantly with the administration of FXR and GPBAR1 double agonists INT-767. The expression of GPBAR1 significantly decreased in Fxr^–/– mice and the GLP-1 secretion did not increase significantly after INT-767 stimulation [59]. The fact indicates that both FXR and GPBAR1 take part in GLP-1 secretion, and FXR plays a critical role [59]. According to research, the promoter of GPBAR1 gene contains an FXR-responsive element (FXRE). FXR can bind with FXRE after being activated by INT-767, thus inducing the GPBAR1 gene expression and increasing Ca²⁺ level and cAMP activity in L cells, subsequently stimulating GLP-1 secretion and improving hepatic glucose and lipid metabolism in HFD-fed mice [59]. FEX can also activate intestinal FXR in db/db mice, resulting in the reorganization of gut flora, the change of bile-acid composition, with the increase of LCA and taurolithocholic acid (TLCA) levels [60]. Consequently, GPBAR1 was activated, and GLP-1 secretion increased, resulting in improved glucose and insulin sensitivity in the liver [60]. In summary, FXR and GPBAR1 have a cross-talk in promoting GLP-1 secretion by L cells and regulating glucose and lipid metabolism (Fig. 3).

Intestinal FXR-cAMP-GLP1 signal pathway

The proximal stomach is cut off, making a stomach pouch (~30 mL) that was anastomosed to the jejunum to reshape the digestive tract, and then intestinal continuity is reconstructed via jejunostomy [61]. Because the newly constructed digestive tract bypasses the majority of the stomach, duodenum, and proximal jejunum, food intake and nutrient absorption are limited. This is the Roux-en-Y gastric bypass (RYGB). Following RYGB, bile and pancreatic secretions were excreted through the foregut and merged into the middle and distal jejunum via the newly established jejunojejunostomy [62]. Clinical investigations have indicated the body mass index and fasting blood glucose of obese patients decreased significantly 15 months after RYGB, accompanied by the increase in fasting plasma total BAs and GLP-1 levels [63]. However, the specific mechanism is unknown. Glucose-stimulated GLP-1 secretion was weakened in Fxr^–/– compared to Fxr^+/+ mice at 4 weeks after RYGB in HFD-induced obese mice, which suggests the FXR-GLP-1 signaling pathway might contribute to glycemic control during the early postoperative period [64]. Bile diversion to the ileum (GB-IL) also improved metabolic function in obese rats, the same as RYGB. Studies have shown that GB-IL can reduce body weight and improve glucose tolerance in Gpbar1^–/– HFD-fed mice but not in Fxr^ΔIE or Glp-1r^–/– mice. It indicates that GB-IL can change the bioavailability of intestinal BAs, activate the FXR-GLP-1 axis, and improve glucose tolerance and body weight [65], suggesting that the improvement in postoperative metabolism in mice depends on the bile-acid signaling pathway mediated by intestinal FXR (Fig. 3).

Intestinal FXR-FGF19/15-SHP-SREBF2-NPC1L1 signal pathway

The NPC1-like intracellular cholesterol transporter (NPC1L1) is highly expressed in the jejunum and ileum [66]. It is a transmembrane transporter located in the apical side of intestinal epithelial cells, in charge of the rate-limiting transport of cholesterol in diet and bile [67-69]. It is also the target for the lipid-lowering drug ezetimibe [67-69]. NPC1L1 expression in the intestine of wild-type mice decreased after fasting and refeeding, while there was no change in Shp^–/– or Fgf15^–/– mice [70]. Injecting FGF19 into mice phosphorylates SHP(Thr-55), inhibiting the sterol regulatory element-binding factor 2 (SREBF2) activity and reducing the intestinal NPC1L1 expression [70]. Finally, it reduces cholesterol absorption in the intestine and further improves hypercholesterolemia [70]. Feeding barley has been shown to significantly decrease the concentration of total plasma cholesterol and low-density lipoprotein cholesterol in HFD-fed mice and increase fecal cholesterol excretion [71]. Feeding barley induces a high expression of intestinal FXR, inhibiting the expression of intestinal NPC1L1 and reducing the uptake of cholesterol in the diet [71] (Fig. 3).

Differential Analysis of Inhibiting or Activating Intestinal FXR on Glucose and Lipid Metabolism

As mentioned earlier, inhibiting or activating intestinal FXR can improve glucose and lipid metabolism in HFD-fed obese mice by the FXR-FGF15/19 pathway. In HFD-induced obese mice, the gut microbiota changes, BSH activity decreases, intestinal bile-acid composition changes, TβMCA or TUDCA increases, the intestinal FXR is inhibited, and the content of intestinal and circulating FGF15 decreases after intragastric administration of Tempol or metformin. This causes an increase in CYP7A1 expression or activity in the liver as negative feedback, followed by a decrease in substrate cholesterol level and improvement in obesity and insulin resistance [36, 37]. The CYP7B1 expression in the liver was upregulated, CDCA synthesis increased, intestinal GCA decreased, and TβMCA increased, causing the inhibition of the intestinal FXR-FGF15/19 axis. Further hepatic lipid synthesis decreased, and heat production in subcutaneous white adipose tissue increased when HFD-fed hamsters were given antibiotics by gavage [38]. It can also improve obesity and insulin sensitivity. On the contrary, the ileum FXR was activated, FGF15 level in the ileum and blood increased. Subsequently, CYP7A1 expression decreased, and CYP7B1 expression increased in the liver, followed by increased CDCA synthesis in the liver, decreased tauro-cholic acid (TCA), and increased LCA in blood, increased BAT energy consumption, WAT browning, and decreased liver glucose and lipid contents when HFD-fed mice were given FEX by gavage [56]. This discrepancy could be due to the following factors after analysis: 1) Different organs affecting the changes of bile-acid composition (intestine and liver) and different orders activating molecules (BA-FXR-FGF15 and FXR-FGF15-BA), implying that BAs can regulate glucose and lipid metabolism by FXR and BAs synthesis can be regulated by FXR. Tempol, metformin, or antibiotics administration affects the intestinal flora first, then the composition of intestinal BAs, inhibiting FXR-FGF15 and improving glucose and lipid metabolism [36-38]. After the FEX administration, FXR-FGF15 is activated first, then hepatic bile-acid synthesis is affected, LCA level increases, and glucose and lipid metabolism is affected by FGF15 or LCA [56]; 2) Intestinal flora factors. Studies have shown that intestinal enzymes (microbial) are involved in BAs modification, including de-binding, transport, and 7α/β-dehydroxylation [72]. Oral antibiotics and FEX can upregulate CYP7B1 and increase CDCA synthesis in the liver [38, 56]; however, oral antibiotics increase intestinal TβMCA [38], oral FEX increases intestinal LCA [56], and the difference in the intestinal flora may play a critical role; 3) Multiple factors are involved in regulation. According to Sun et al. [37], TUDCA or GUDCA can promote GLP-1 secretion. Fang et al. [56] mentioned that FGF15 is just a factor, and the effect of LCA-GPBAR1 or other unknown signal pathways on the improvement of glucose and lipid metabolism caused by FEX cannot be ruled out.

Similarly, the above-mentioned intestinal FXR inhibition or activation can promote the increase of GLP-1. The following are possible explanations for the differences: 1) Different intestinal agonists. Oral intake of nonspecific FXR agonist GW4064 in mice can reduce glycolysis, consequently lower GLP-1 production by reducing the transcription factor ChREBP expression, and decrease GLP-1 secretion by reducing ATP production [49]. Oral administration of intestinal specific FXR agonist FEX can activate intestinal FXR, change the intestinal flora, change intestinal bile-acid composition, increase LCA and TLCA, and promote GLP-1 secretion by GPBAR1 activation [60]. Activated FXR induced GPBAR1 gene expression and increased cAMP and GLP-1 secretion in mice receiving FXR and GPBAR1 double-agonists INT-767 by gavage [59]. By directly activating FXR, nonspecific FXR agonists inhibit GLP-1 production and secretion. Intestinal specific FXR agonists, FXR and GPBAR1 double agonists increase GLP-1 secretion by indirectly activating GPBAR1. 2) The differences between in vivo and in vitro experiments. In vitro GW4064 given to STC-1 cells activated FXR, inhibited CREBP transcription activity, and decreased PC level and GLP-1 secretion [54]. Oral administration of FEX or surgical shunting of BAs to the ileum activated intestinal FXR, modified intestinal flora and BAs, and elevated GLP-1 secretion [60, 65]. In vitro, it is the change of a single stimulus to a single cell. In vivo, there are many factors involved in regulation. The results may vary between vivo and vitro conditions. 3) The experimental conditions are different. FXR knockout causes the up-regulation of the colon Ffar2 gene, the activation of downstream Ca²⁺/IP3, and further the increase of SCFA-stimulated GLP-1 secretion in mice of HFD and ITF administered simultaneously [52]. ITF may cause FXR-FFAR2-Ca²⁺/IP3-GLP-1 pathway activation under specific conditions [52]. After oral administration of INT-767 or FEX to mice, FXR activation directly or indirectly activated GPBAR1 and increased GLP-1 secretion [59, 60].

BAs Affect Glucose and Lipid Metabolism by GPBAR1

GPBAR1 is a transmembrane G protein-coupled BA receptor. It is found in lots of organs and tissues and is highly expressed in the small intestine, stomach, liver, lung, placenta, and spleen [73, 74]. At present, BAs are the only endogenous ligand of GPBAR1. Secondary BAs have higher GPBAR1 affinity than primary BAs. The ability of BAs to activate GPBAR1 is TLCA > LCA > DCA > CDCA > CA [75].

BAs affect glucose and lipid metabolism by activating the GPBAR1-cAMP-DIO2 signal pathway

Severe metabolic syndrome, like obesity, insulin resistance, and glucose and lipid metabolism disorder, are shown in Gpbar1^–/– mice [76]. CA feeding has been demonstrated to reverse obesity in HFD-fed mice. The mechanism is dependent on GPBAR1, which activates BAT thermogenesis and thyroxine signaling pathway, hence increasing energy consumption [77]. GPBAR1 activates the cAMP signaling pathway and induces the thyroid hormone deiodinase 2 (Dio2) gene expression in BAT, promoting the conversion of thyroxine to triiodothyronine and increasing energy consumption. In addition to Dio2, thermogenic genes, such as Pgc1α, Pgc1β, Ucp1, Ucp3, and straight-chain acyl-CoA oxidase 1 were significantly upregulated, whereas Dio2^–/– mice showed no such change [77]. Administration of TCA and DCA activated GPBAR1 and upregulated expression of UCP1 and mitochondrial creatine kinase 2, resulting in elevation of WAT thermogenesis and remission of obesity in mice fed a HFD [78]. The regulation of BA on glucose and lipid metabolism could be studied using the mouse bile diversion model, which anastomoses the gallbladder to the distal jejunum. After bile diversion surgery, the metabolic phenotype of obese mice was improved, and energy consumption increased. Moreover, the expression of Gpbar1, Dio2, thermogenic gene Ucp1, PR domain-containing 16, Pgc-1α, Pgc-1β, alpha-type platelet-derived growth factor receptor in epididymal and inguinal WAT increased, and the F/B ratio of gut microbiota decreased [79]. BAs can influence energy metabolism by activating the GPBAR1-cAMP-DIO2 signaling pathway (Fig. 3).

BAs affect glucose and lipid metabolism by activating the intestinal GPBAR1-cAMP-GLP1 signal pathway

Administration of GPBAR1-specific agonist INT-777 (CDCA derivative) in HFD-fed obese mice can increase GLP-1 secretion, accompanied by improved hepatic steatosis, obesity, and insulin sensitivity. However, GLP-1 level is not significantly elevated in Gpbar1^–/– mice [80]. Bile acid treatment activates GPBAR1, initiates the cAMP signaling pathway, increases Ca²⁺ influx, and stimulates GLP-1 secretion in STC-1 cells [80]. After being treated with bile acid-binding resins colestipol, wild-type mice have shown increased serum GLP-1 level, improved glucose tolerance, along with increased intestinal PC1/3 gene expression compared to Gpbar1^–/– mice [81]. Bile acid-binding resins can change the BAs composition in the gut, such as increasing TCA (GPBAR1 agonist) level, and thus increase intestinal GPBAR1 activity. Subsequently, the nuclear factor of activated T cells (NFAT) binds to the intestinal PC1/3 promoter region to promote the PC1/3 expression and GLP-1 release, accompanied by significant improvement in glucose tolerance [81]. The cAMP-PKA-Ca²⁺/calmodulin-calcineurin-NFAT-PC1/3 signaling pathway may be involved in GPBAR1 agonists-induced GLP-1 release [81]. A recent study shows that HCA and its derivatives are present in trace amounts in human blood but are the primary BAs in pigs, a species known for its exceptional resistance to type 2 diabetes [82]. In vivo and in vitro, HCA promoted GLP-1 production and secretion in enteroendocrine cells through concurrently activating GPBAR1 and inhibiting FXR, and improved glucose homeostasis [82] (Fig. 3).

Colesevelam (3.75 g/day for 12 weeks), a non-absorbed BAs sequestrant, increased fasting and postprandial total GLP-1 concentrations, enhanced cholesterol and BAs synthesis (including CA and CDCA), decreased both fasting and postprandial FGF19 levels and improved HOMA-beta cell function in a randomized controlled study of T2DM. However, no effect was seen on fractional hepatic de novo lipogenesis [83]. Colesevelam (3.75 g/day for 12 weeks) was found to increase fast total GLP-1 but not postprandial total GLP-1 levels while decreasing fasting and postprandial glucose levels [84]. A recent study found that bile acid-sequestering resin sevelamer slightly increased fasting plasma GLP-1 and GLP-1 AUC_{0–240 min} while significantly decreasing CDCA AUC_{0–240 min} (standardized 4-hr liquid meal tests) and DCA AUC_{0–240 min} in patients with T2DM. Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reductions in plasma cholesterol and FGF19 concentrations, increased de novo bile acid synthesis, a shift towards a more hydrophilic bile acid pool, and increased lipogenesis with elevated plasma triglycerides in an FXR- and LXRα-dependent manner [85]. The mechanisms of BAs sequestrants on GLP-1 secretion include GPBAR1-dependent and GPBAR1-independent; the former involves that intestine luminal BAs [primarily LCA and taurolithocholic acid (TLCA)] activate TGR5, while the latter refers that the fatty acids reaching the ileum induce GLP-1 secretion via G protein-coupled free fatty acid receptors (FFAR) on the L cells [86]. Therefore, bile acid sequestrants increased fasting plasma GLP-1 levels due to an increase in specific BAs in the bowel lumen, such as TCA, LCA, and TLCA (Fig. 3).

BAs affect glucose and lipid metabolism by activating the intestinal GPBAR1-mTORC1-GLP-1 signal pathway

The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase, which includes two complexes, namely mTOR complex 1 (mTORC1) and mTOR complex 2. Ribosomal protein S6 kinases, S6, and eukaryotic translation initiation factor 4E binding protein 1 are among its downstream target proteins [87-89]. The mTOR signaling pathway promotes material metabolism and participates in cell apoptosis and autophagy. The abnormal activation is associated with diabetes, obesity, and cancer [89, 90]. Compared to mTOR complex 2, mTORC1 plays a more important role, primarily responsible for nutritional perception [88]. Animal and cell experiments show that intestinal mTORC1 participates in regulating the synthesis of GLP-1 in L cells [91]. After RYGB in mice and humans, circulating BAs increased, ileal GPBAR1 and mTORC1 signaling pathways were activated, and GLP-1 synthesis and secretion were elevated [92]. In vitro, DCA significantly enhanced the GPBAR1-mTORC1 signal, followed by increased phosphorylation of mTOR, S6K, and S6, and enhanced GLP-1 synthesis and secretion in STC-1 cells. After the knockdown of GPBAR1 or mTORC1, the increased effect of DCA-induced GLP-1 synthesis disappeared [92] (Fig. 3).

BAs Affect Glucose and Lipid Metabolism through Other Mechanisms

BAs regulate liver insulin sensitivity

The plasma BAs level increased significantly after DCA was perfused into the jugular vein of wild-type mice. The increase in plasma BAs damaged the hepatic insulin sensitivity by restricting the inhibitory effect of insulin on hepatic glucose production. It was also observed in Gpbar1^–/– mice, implying that an acute increase in BAs in circulation can affect hepatic insulin sensitivity indirectly, independent of the GPBAR1 signal pathway [93]. However, clinical studies have shown that TUDCA improves insulin sensitivity in the liver and muscle and increases muscle insulin signal transduction in obese men and women [94].

BAs promote GLUT4 expression in adipocytes and hepatocytes

Glucose transporter 4 (GLUT4) is expressed exclusively in insulin target tissues like BAT, WAT, skeletal muscle, and heart and is critical for maintaining systemic glucose homeostasis [95, 96]. FXR and FXR agonist CDCA promoted GLUT4 transcription in 3T3-L1 and HepG2 cells in vitro. FXR combined with FXRE in the GLUT4 promoter region to induce GLUT4 expression and participate in the regulation of glucose homeostasis [97].

BAs stimulate insulin secretion of pancreatic β-cells

TCDCA activates FXR of mouse pancreatic β-cells, inhibits the activity of sulfonylurea receptor 1 (SUR1), a subunit of the ATP-sensitive potassium channel, decreases K⁺ outflow, and increases cytoplasmic Ca²⁺ concentration and the following insulin secretion. TCDCA does not change insulin secretion of islet β-cells in Sur1^–/– or Fxr^–/– mouse [98].

BAs modulate inflammatory regulator nuclear factor-κB and inhibitory kappa B kinase

CDCA has been demonstrated to improve adipokine secretion in 3T3-L1 cells treated with palmitate and adipose tissues of HFD-fed mice. CDCA inhibits their activation by suppressing the phosphorylation of inflammatory regulators (nuclear factor-κB and inhibitory kappa B kinase), thereby inhibiting the secretion of pro-inflammatory adipokines, such as tumor necrosis factor-a, interleukin-6, monocyte chemotactic protein-1, and enhancing the secretion of anti-inflammatory adipokines (adiponectin and leptin); thus, it alleviates insulin resistance [99]. Administration of DCA reduces inflammation and improves heart function post-myocardial infarction via activating GPBAR1, and inhibiting nuclear factor-κB signaling and subsequent IL-1β expression in mice [100].

BAs regulate intracellular oxidative stress

The effect of hydrophobic BAs (The overall hydrophobicity is the following: UDCA < CA < CDCA < DCA < LCA), in particular, can be linked with cancer through a series of complex mechanisms including direct oxidative stress with DNA damage, apoptosis, epigenetic factors regulating gene expression [101]. Studies have shown that glyco-chenodeoxycholic acid stimulated cytotoxicity, increased reactive oxygen species (ROS) production, and decreased mitochondrial mass and mitochondrial DNA content in L02 cells [102]. DCA and CDCA promoted cell death in BCS-TC2 human colon adenocarcinoma cells due to oxidative stress with increased ROS generation [103]. However, some bile acids, such as UDCA, also exert beneficial effects by reducing oxidative stress in regulating glucose and lipid metabolism. Studies have demonstrated that palmitate increased ROS and significantly inhibited insulin-induced AKT phosphorylation in HepG2 cells; UDCA combined with insulin treatment can decrease the level of intracellular ROS, and UDCA treatment partially restores PI3K/AKT phosphorylation inhibited by palmitate [104]. UDCA has been shown to improve the abnormality of glucose and lipid metabolism in rats (induced by fructose), lower uric acid levels, ameliorate insulin resistance and reduce the oxidative stress of vascular tissue [105].

BAs regulate endoplasmic reticulum stress

Endoplasmic reticulum stress (ER stress) has been shown to be involved in the induction and development of various pathogenic conditions. CDCA induced ER stress and stimulated apoptosis in HepG2 cells [106]. BAs (especially DCA) elevated by HFD could trigger ER stress in intestinal stem cells and disrupt the intestinal mucosal barrier [107]. On the other hand, ER stress is a key link between obesity, insulin resistance, and type 2 diabetes. GUDCA alleviated ER stress in livers of HFD-fed mice without alteration of liver metabolism and palmitic acid induced-ER stress and -apoptosis in HepG2 cells [108]. TUDCA can reduce ER stress in mice with obesity and type 2 diabetes, improve hyperglycemia and insulin resistance, and enhance insulin effects in the liver, muscle, and adipose tissue [109]. UDCA can inhibit ER stress in db/db mice, restore autophagy, and improve the biochemical index of diabetes nephropathy [110]. Different BAs have different effects on ER stress, especially in different experimental conditions.

BAs regulate intestinal inflammation, intestinal barrier, and intestinal lipid absorption & transport

In murine colitis models, fecal secondary BAs were increased, and DCA supplementation induced intestinal inflammation [111, 112]. In contrast, DCA/LCA supplementation via rectal administration showed anti-inflammatory effects partly dependent on GPBAR1 signaling in three murine colitis models, which is consistent with the depletion of secondary BAs in inflammatory bowel disease patients [113, 114]. Curiously, DCA exerted both pro- and anti-inflammatory effects in these studies, which might be due to different routes of administration and different types of colitis models. LCA showed a significant protective effect on TNF-α-induced injury of intestinal barrier function in Caco-2 cells [115]. In HFD-fed mice, TUDCA can reduce hepatic steatosis and inflammation, obesity, and insulin resistance. TUDCA can also relieve intestinal inflammatory response, improve intestinal barrier function, reduce intestinal lipid transport genes, like a cluster of differentiation 36, fatty acid-binding protein, fatty acid transport protein 4, and fatty acid receptor 3, and then reduce HFD-induced NAFLD [116]. Under normal chow conditions, the synthesis and secretion of 12α-OH BAs into the intestinal cavity of the proximal small intestine in Cyp8b1^–/– mice have been shown to be decreased compared with wild-type mice. Consequently, the ability to emulsify lipids was weakened, and triglyceride hydrolysis and hydrolysate uptake in the proximal small intestine were reduced, resulting in an increase in triglycerides and hydrolysates FFA and 2-monoacylglycerol transported to the distal small intestine. In the distal ileum, 2-monoacylglycerol induces GLP-1 secretion by activating GPR119, improving body weight and blood glucose by slowing down gastric emptying and food intake [117]. Different effects of BAs in these studies might result from different types of disease models and different dysregulation of BA homeostasis.

Inhibition of BA uptake protects against obesity and hepatic steatosis

Asbt^–/– mice are resistant to hepatic steatosis with short-term (1w) HFD feeding compared to wild-type mice [118]. Administration of ASBT inhibitor (SC-435) impaired ileal BA uptake in HFD-fed mice, reduced mRNA expression of ileal BA-responsive genes, including the negative feedback regulator of BA synthesis FGF15, and subsequently increased BA synthesis in the liver. ASBT inhibition resulted in a remarkable shift in hepatic BA composition, with a reduction in hydrophilic, FXR antagonistic species and an increase in FXR agonistic BAs (TCDCA and TDCA), accompanied by a reduced hepatic expression of lipid synthesis genes (Srebp1c, Scd1, etc.). Finally, ASBT inhibition restored glucose tolerance, reduced hepatic triglyceride and total cholesterol contents, and improved NAFLD Activity Score in HFD-fed mice [118]. NTCP deficiency reduced hepatic clearance of bile acids from plasma, increased plasma BA levels, and prevented body weight gain and hepatic steatosis in HFD-fed mice. These changes are due to decreased intestinal fat absorption and increased energy expenditure via increased BAT thermogenesis [119]. BA uptake transporters ASBT and NTCP are potential therapeutic targets for obesity and NAFLD [120].

BAs regulate the balance of peripheral T cells and maintain intestinal immune homeostasis

In vitro, CA, CDCA, DCA, LCA, and ωMCA are cytotoxic to wild-type T cells at or above their critical micelle concentration (about 2.5–10 mM) and can inhibit the efflux of heterotypic substances mediated by multidrug resistance protein 1 (MDR1), a membrane-related and ATP-dependent efflux pump used to transport chemotherapeutic drugs out of tumor cells. In mice receiving MDR1-deficient T cells, cholestyramine, a bile-acid sequestration, restores intestinal homeostasis [121]. In vivo and in vitro, 3β-hydroxydeoxycholic acid (isoDCA) increases the induction of transcription factor forkhead box P3 by reducing the immune stimulation characteristics of dendritic cells, resulting in increased proliferation of peripheral regulatory T cells and maintaining colonic immune homeostasis [122].

Conclusions

The ability of BAs to regulate glucose and lipid metabolism as signal molecules has received a lot of attention. This study reviews the synthesis, circulation, and regulation of BAs and their effects on glucose and lipid metabolism by acting on FXR in the liver, and FXR and GPBAR1 in the intestine. It further explains that FGF15/19, ceramide, and GLP-1 are all involved in the signaling pathways by which BAs regulate glucose and lipid metabolism, and maybe serve as a foundation for future scientific and clinical research. Different types of BAs, different organs of action, different activated receptors, and the following different activated downstream signal pathways result in different impacts. The final result may be due to the competition of several different signal pathways under specific environmental factors. Further studies are required to give people a more comprehensive understanding of the molecular mechanisms that BAs regulate glucose and lipid metabolism, which is essential for searching for drug targets alleviating glucose and lipid metabolic disorders.

Abbreviations

NAFLD, non-alcoholic fatty liver disease; BAs, bile acids; FXR, farnesoid X receptor; GPBAR1, cell surface-located G protein-coupled bile acid receptor 1, also known as TGR5; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP7A1, cytochrome P450 family 7 subfamily A member 1; CYP8B1, cytochrome P450 family 8 subfamily B member 1; CYP27A1, cytochrome P450 family 27 subfamily A member 1; CYP7B1, cytochrome P450 family 7 subfamily B member 1; UDCA, ursodeoxycholic acid; MCAs, muricholic acids; BSH, bile acid salt hydrolysis enzyme; DCA, deoxycholic acid; LCA, lithocholic acid; HCA, hyocholic acid; MDCA, murideoxycholic acid; HDCA, hyodeoxycholic acid; ATP, adenosine triphosphate; BSEP, bile salt export protein; ASBT, apical sodium dependent bile acid transporter; OSTα/β, organic solute transporter α/β; NTCP, sodium taurocholate co-transporting polypeptide; SHP, small heterodimer partner; FGF15/19, fibroblast growth factor 15/19; ERK, extracellular signal-regulated kinase; AMPK, adenosine monophosphate activated protein kinase; SIRT1, sirtuin 1; DCoH2, dimerization cofactor of hepatocyte nuclear factor 1a 2; HNF-1a, hepatocyte nuclear factor 1a; TαMCA, tauro-alpha-muricholic acid; TβMCA, tauro-beta-muricholic acid; SREBP-1c, sterol regulatory element-binding protein 1c; SCD-1, stearoyl coenzyme A desaturase-1; HNF4α, hepatocyte nuclear factor-4 alpha; FOXO1, forkhead box protein O1; HFD, high-fat diet; TUDCA, tauro-ursodeoxycholic acid; SMPD3, sphingomyelin phosphodiesterase 3; WAT, white adipose tissue; BAT, brown adipose tissue; Gly-MCA, glycine-β-muricholic acid; GUDCA, glyco-ursodeoxycholic acid; ER, endoplasmic reticulum; PC, pyruvate carboxylase; GLP-1, glucagon-like peptide-1; PC1/3, prohormone convertases 1/3; ChREBP, carbohydrate responsive element-binding protein; SCFA, short-chain fatty acids; ITF, inulin-type fructans; FFAR2, SCFA receptor 2; IP3, inositol tri-phosphate; FFA, free fatty acids; cAMP, cyclic adenosine monophosphate; CREBP, cAMP response element‐binding protein; FEX, fexaramine; UCP1, uncoupling protein 1; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α; FXRE, FXR-responsive element; TLCA, tauro-lithocholic acid; RYGB, Roux-en-Y gastric bypass; GB-IL, bile diversion to the ileum; NPC1L1, NPC1-like intracellular cholesterol transporter; SREBF2, sterol regulatory element-binding factor 2; TCA, tauro-cholic acid; DIO2, deiodinase 2; NFAT, nuclear factor of activated T cells; mTOR, the mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; GLUT4, glucose transporter 4; SUR1, sulfonylurea receptor 1; ROS, reactive oxygen species; ER stress, endoplasmic reticulum stress; MDR1, multidrug resistance protein 1

Acknowledgments

This study was financially supported by a grant from the Natural Science Foundation of Shandong Province, China (NO: ZR2021QH362). We thank Editeg Culture Communication Co., LTD for providing the English grammar editing service.

Conflict of Interest Disclosure

The author has no competing interests to disclose.

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