Desmosterol as a Novel Biomarker Linking Cholesterol Metabolism, Liver Inflammation, and Cardiovascular Risk in Metabolic Dysfunction-Associated Steatotic Liver Disease

Abbreviations: metabolic dysfunction-associated steatotic liver disease, MASLD; nonalcoholic fatty liver disease, NAFLD; metabolic dysfunction-associated steatohepatitis, MASH; atherosclerotic cardiovascular disease, ASCVD; Mac-2 binding protein glycosylation isomer, M2BPGi; cytokeratin-18 fragment, CK-18F; Δ24-dehydrocholesterol reductase, DHCR24; liver X receptor, LXR; liquid chromatography-mass spectrometry, LC-MS/MS

See article vol. 33: 29-39

Metabolic dysfunction-associated steatotic liver disease (MASLD), recently redefined from nonalcoholic fatty liver disease (NAFLD), is now among the most prevalent liver disorders, affecting up to 30% of adults in both Asia and Western countries. Its spectrum ranges from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Beyond hepatic morbidity, MASLD is increasingly recognized as a systemic disease closely linked to type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (ASCVD), which is the leading cause of death in this population¹⁾. Consequently, identifying noninvasive biomarkers that capture both hepatic inflammatory activity and systemic metabolic risk has become a major unmet need in hepatology.

Fibrosis stage remains the most powerful histological predictor of outcomes²⁾, and simple noninvasive scores such as the FIB-4 index are widely used³⁾. Additional biomarkers, including Mac-2 binding protein glycosylation isomer (M2BPGi)⁴⁾ and cytokeratin-18 fragment (CK-18F)⁵⁾, together with imaging modalities like vibration-controlled transient elastography⁶⁾ have further refined fibrosis assessment⁷⁾ (Table 1). However, these indices primarily reflect tissue remodeling or stiffness rather than the metabolic and inflammatory dynamics driving disease progression. Given that MASLD is fundamentally a disorder of lipid and cholesterol metabolism, biomarkers reflecting hepatocellular lipid flux may yield earlier and more mechanistic insights into disease activity.

Table 1.Major Non-Invasive Tests for MASLD in Japan

Category	Non-Invasive Tests	Main Strengths	Main Limitations
Scoring System	FIB-4 Index	・Simple, inexpensive, and widely validated ・High negative predictive value for advanced fibrosis ・Recommended as a first-line triage tool	・Low positive predictive value in the general population ・Reduced accuracy in elderly, obese, and diabetic patients ・Presence of an indeterminate zone
	NAFLD Fibrosis Score (NFS)	・Based on routine laboratory data ・Endorsed by the EASL and AASLD ・Useful for risk stratification in patients with T2D	・Complex formula ・Low accuracy in obese and elderly individuals ・Presence of an intermediate zone
Biomarker	Type 4 Collagen 7S (T4C7S)	・Widely available in Japan ・Reflects fibrogenesis ・Inexpensive	・Limited global validation
	Hyaluronic Acid (HA)	・Established fibrosis marker ・Applicable in pediatric MASLD	・Elevated in renal disease, arthritis, or cancer
	Autotaxin (ATX)	・Detects early fibrosis ・Less influenced by inflammation	・Sex-dependent values ・Limited availability outside Japan
	Cytokeratin-18 Fragment (CK-18F)	・Marker of hepatocyte apoptosis ・Approved for MASH in Japan	・Variable cutoff values ・ Limited validation ・Moderate accuracy
	Mac-2 Binding Protein Glycosylation Isomer (M2BPGi)	・High diagnostic accuracy for advanced fibrosis ・Age-independent cutoff values ・Potential predictor of HCC	・Disease-specific thresholds ・Unclear mechanism ・Requires a proprietary analyzer
	Enhanced Liver Fibrosis (ELF) Test	・Noninvasive and repeatable ・Approved by the FDA as a MASH prognostic marker ・Recently approved in Japan	・Limited Japanese data ・Special equipment required
Elastography	Vibration-Controlled Transient Elastography (VCTE)	・Quantifies liver stiffness ・Well validated ・Portable and widely used	・Limited in severe obesity or ascites ・Operator-dependent ・Cutoff values vary by etiology
	Shear Wave Elastography (SWE)	・Integrated in ultrasound systems ・High reproducibility ・Assesses both elasticity and dispersion	・Requires expertise ・Differences among vendors ・Limited long-term validation
	Magnetic Resonance Elastography (MRE)	・Most accurate noninvasive imaging for liver fibrosis ・Whole liver evaluation ・Minimal interobserver variation	・High cost ・Limited accessibility ・Not suitable for all patients

MASLD, metabolic dysfunction-associated steatotic liver disease; FIB-4, fibrosis-4; NAFLD, nonalcoholic fatty liver disease; EASL, European Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; T2D, type 2 diabetes mellitus; MASH, metabolic dysfunction-associated steatohepatitis; HCC, hepatocellular carcinoma

In this issue of J Atheroscler Thromb, Omatsu and colleagues report that serum desmosterol, a cholesterol synthesis intermediate converted by Δ24- dehydrocholesterol reductase (DHCR24), correlates with histological inflammation grade in biopsy-proven MASLD⁸⁾. In their cohort of 217 Japanese patients with moderate obesity (mean BMI, 30.1±6.3 kg/m²), serum desmosterol levels increased progressively with lobular inflammation grade, showing a positive correlation. Multivariate analyses confirmed desmosterol as an independent determinant of inflammation, with an odds ratio of 3.727, even after adjustment for cholesterol, liver enzymes, and metabolic parameters. The association persisted in non-statin-treated patients, underscoring its robustness beyond lipid-lowering therapy. In contrast, total and LDL cholesterol, as well as cholesterol absorption markers such as sitosterol and campesterol, showed no correlation with inflammation grade. These findings highlight desmosterol as a metabolic mirror of hepatic inflammation, integrating cholesterol synthesis flux with immune-metabolic signaling. Mechanistically, desmosterol acts as an endogenous ligand of liver X receptors (LXRs), nuclear receptors that regulate lipid metabolism, reverse cholesterol transport, and inflammatory gene expression⁹⁾. Experimental studies have shown that desmosterol accumulation in macrophages suppresses inflammasome activation and atherosclerosis, whereas its depletion promotes inflammatory signaling¹⁰⁾. In hepatocytes, modulation of DHCR24 activity alters both lipid homeostasis and cytokine expression, linking cholesterol metabolism to inflammatory cascades¹¹⁾. Thus, elevated desmosterol may not simply mark increased cholesterol synthesis but instead reflect a compensatory anti-inflammatory response to metabolic stress within the liver.

Interestingly, Omatsu et al. found no correlation between desmosterol and fibrosis stage, steatosis, or ballooning⁸⁾. This suggests that desmosterol primarily captures dynamic inflammatory activity rather than chronic scarring. Clinically, this distinction is crucial. Fibrosis represents the cumulative consequence of past injury, whereas inflammation reflects ongoing metabolic stress and indicates the potential for disease progression or reversibility. In this context, desmosterol could serve as an upstream marker of disease activity, identifying patients at risk before irreversible fibrosis develops. These findings have significant clinical implications. First, as a noninvasive biomarker, desmosterol could complement fibrosis-based indices and imaging modalities by providing a real-time reflection of hepatic inflammation. Second, because desmosterol is functionally linked to macrophage lipid metabolism and LXR signaling¹⁰⁾, it may also act as a shared biomarker that bridges hepatic and vascular inflammation, effectively connecting MASLD and ASCVD biology. This dual relevance is especially compelling given that cardiovascular disease, rather than liver failure, remains the leading cause of mortality in MASLD¹⁾. Third, desmosterol could serve as both a pharmacodynamic biomarker and therapeutic target. Statins lower desmosterol levels, reflecting inhibition of cholesterol synthesis⁸⁾, whereas experimental DHCR24 inhibitors increase desmosterol while reducing hepatic lipid accumulation and inflammation in animal models¹¹⁾. These opposing effects highlight the dual relevance of desmosterol as a marker of therapeutic response and a potential target for modulating hepatic metabolic and inflammatory pathways.

Nevertheless, several challenges remain before clinical translation. Quantification of desmosterol currently relies on liquid chromatography-mass spectrometry (LC-MS/MS), which is not routinely available in clinical laboratories. Simplified enzymatic or immunoassay-based detection methods will be needed for broader application. Reference ranges stratified by age, sex, and medication use should be established, given physiological variation. Pharmacologic confounders such as statin therapy must also be carefully considered when interpreting results. Direct comparison with existing inflammatory biomarkers (e.g., CK-18F and high-sensitive CRP) is required to define the diagnostic accuracy and clinical relevance of desmosterol.

Mechanistic uncertainties also persist regarding whether elevated desmosterol is a cause or consequence of hepatic inflammation. Two plausible models can be envisioned. In a compensatory model, hepatic inflammation increases desmosterol, which exerts an LXR-mediated anti-inflammatory effect as part of a homeostatic response. In contrast, a driver model proposes that local desmosterol accumulation modulates inflammatory signaling in hepatocytes and macrophages, thereby influencing hepatic inflammatory activity. The link between desmosterol and hepatic inflammation remains largely correlative rather than causal. To establish causality, it will be crucial to clarify this bidirectional interplay through studies manipulating DHCR24 activity, which regulates desmosterol levels, as well as tracing sterol flux, and analyzing LXR-regulated gene expression. Furthermore, it remains unknown whether desmosterol elevation occurs across different etiologies of liver inflammation (e.g., viral, alcohol-related, or cholestatic). Addressing this question will clarify whether desmosterol functions as a general inflammatory marker or a MASLD-specific indicator.

Despite these challenges, the study by Omatsu et al. represents an important step toward metabolically informed risk stratification in MASLD⁸⁾. By focusing on a cholesterol biosynthetic intermediate rather than a conventional lipid endpoint, the authors open a new window into the interplay between hepatic metabolism, inflammation, and cardiovascular disease. Their work demonstrates how lipidomic profiling can illuminate the metabolic underpinnings of liver inflammation and underscores the potential of desmosterol as both a promising biomarker of hepatic activity and a mechanistic link within the cardio-hepato-metabolic continuum. Future multicenter and longitudinal studies integrating desmosterol with proteomic and imaging markers may ultimately pave the way toward precision risk assessment and holistic management of MASLD.

References

• 1)  Younossi ZM, Paik JM, Stepanova M, Ong J, Alqahtani S, Henry L. Clinical profiles and mortality rates are similar for metabolic dysfunction-associated steatotic liver disease and non-alcoholic fatty liver disease. J Hepatol, 2024; 80: 694-701
• 2)  Fujii H, Iwaki M, Hayashi H, Toyoda H, Oeda S, Hyogo H, Kawanaka M, Morishita A, Munekage K, Kawata K, Yamamura S, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Kawada N, Tokushige A, Kamada Y, Takahashi H, Ueda S, Aishima S, Sumida Y, Nakajima A, Okanoue T; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Clinical outcomes in biopsy-proven nonalcoholic fatty liver disease patients: A multicenter registry-based cohort study. Clin Gastroenterol Hepatol, 2023; 21: 370-379
• 3)  Sumida Y, Yoneda M, Hyogo H, Itoh Y, Ono M, Fujii H, Eguchi Y, Suzuki Y, Aoki N, Kanemasa K, Fujita K, Chayama K, Saibara T, Kawada N, Fujimoto K, Kohgo Y, Yoshikawa T, Okanoue T; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol, 2012; 12: 2
• 4)  Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, Hara Y, Hige S, Sakamoto M, Yamada G, Kage M, Korenaga M, Hiasa Y, Mizokami M, Narimatsu H. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol, 2015; 50: 776-784
• 5)  Kawanaka M, Kamada Y, Takahashi H, Iwaki M, Nishino K, Zhao W, Seko Y, Yoneda M, Kubotsu Y, Fujii H, Sumida Y, Kawamoto H, Itoh Y, Nakajima A; Japan Study Group of NAFLD (JSG-NAFLD). Serum cytokeratin 18 fragment is an indicator for treating metabolic dysfunction-associated steatotic liver disease. Gastro Hep Adv, 2024; 3: 1120-1128
• 6)  Cassinotto C, Boursier J, de Lédinghen V, Lebigot J, Lapuyade B, Cales P, Hiriart JB, Michalak S, Bail BL, Cartier V, Mouries A, Oberti F, Fouchard-Hubert I, Vergniol J, Aubé C. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology, 2016; 63: 1817-1827
• 7)  Kamada Y, Nakamura T, Isobe S, Hosono K, Suama Y, Ohtakaki Y, Nauchi A, Yasuda N, Mitsuta S, Miura K, Yamamoto T, Hosono T, Yoshida A, Kawanishi I, Fukushima H, Kinoshita M, Umeda A, Kinoshita Y, Fukami K, Miyawaki T, Fujii H, Yoshida Y, Kawanaka M, Hyogo H, Morishita A, Hayashi H, Tobita H, Tomita K, Ikegami T, Takahashi H, Yoneda M, Jun DW, Sumida Y, Okanoue T, Nakajima A; JANIT Forum. SWOT analysis of noninvasive tests for diagnosing NAFLD with severe fibrosis: an expert review by the JANIT Forum. J Gastroenterol, 2023; 58: 79-97
• 8)  Omatsu T, Koseki M, Ito K, Saga A, Sawabe H, Tanaka K, Inui H, Okada T, Nishida M, Takahashi H, Aishima S, Kamada Y, Yoshida H, Sakata Y. Serum desmosterol level reflects hepatic inflammation grade in patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease. J Atheroscler Thromb, 2026; 33: 29-39
• 9)  Yang C, McDonald JG, Patel A, Zhang Y, Umetani M, Xu F, Westover EJ, Covey DF, Mangelsdorf DJ, Cohen JC, Hobbs HH. Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J Biol Chem, 2006; 281: 27816-27826
• 10)  Zhang X, McDonald JG, Aryal B, Canfrán-Duque A, Goldberg EL, Araldi E, Ding W, Fan Y, Thompson BM, Singh AK, Li Q, Tellides G, Ordovás-Montanes J, García Milian R, Dixit VD, Ikonen E, Suárez Y, Fernández-Hernando C. Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis. Proc Natl Acad Sci U S A, 2021; 118: e2107682118
• 11)  Zhou E, Ge X, Nakashima H, Li R, van der Zande HJP, Liu C, Li Z, Müller C, Bracher F, Mohammed Y, de Boer JF, Kuipers F, Guigas B, Glass CK, Rensen PCN, Giera M, Wang Y. Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation. EMBO Mol Med, 2023; 15: e16845

Related Articles

• https://doi.org/10.5551/jat.65748