The circadian rhythm connection in cholestatic liver disease

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are characterized by disrupted bile acid (BA) homeostasis, chronic inflammation, and progressive liver injury. Although circadian rhythms are known to regulate hepatic metabolism, the mechanisms linking circadian disruption to cholestatic liver disease remain poorly understood.

In a recent Genes & Diseases study, researchers from Chongqing Medical University and University College London identified cluster of differentiation 36 (CD36) as a critical regulator connecting circadian rhythm disturbances to abnormal bile acid metabolism and cholestatic liver injury through modulation of the HMGCR/CYP7A1 signaling axis.

Analysis of clinical liver biopsy samples from patients with PBC and PSC revealed that CD36 expression is significantly upregulated in human liver tissues compared to normal controls, showing a positive association with serum markers of liver damage like ALP, GGT, and total bilirubin.

Using bile duct ligation (BDL) mouse models and liver-specific CD36 knockout (CD36 LKO) mice, the investigators demonstrated that cholestatic liver injury profoundly disrupted the rhythmic oscillation of core circadian clock genes, such as Per1, Per2, and Nr1d1 and bile acid metabolism-related genes. BDL mice displayed severe liver injury accompanied by altered rhythmic expression of genes involved in bile acid synthesis, transport, and regulation, including Cyp7a1, Fxr, Bsep, and Mrp2. Importantly, CD36 expression exhibited enhanced diurnal oscillation during cholestatic injury, suggesting that abnormal CD36 activation may contribute directly to circadian metabolic dysregulation.

The study also demonstrated that elevated CD36 expression contributed to inflammatory activation and liver fibrosis. CD36-deficient mice showed markedly reduced expression of inflammatory cytokines, including IL-1β, IL-6, MCP-1, and TNF-α, together with decreased collagen deposition, inflammatory infiltration, and cholangiocyte proliferation. Histological analyses confirmed substantial attenuation of liver injury and fibrosis in CD36 LKO mice compared with BDL controls. These findings establish CD36 as a major mediator linking disrupted circadian rhythms to inflammatory and fibrotic responses in cholestatic liver disease.

To further investigate the role of CD36, the authors performed transcriptomic and metabolic analyses in CD36-deficient mice. Hepatic CD36 deletion significantly restored bile acid metabolic rhythms, normalized the expression of core clock genes, and reduced cholestatic liver damage. Using clustering analysis, the researchers identified two distinct gene expression patterns: the "R-N-R" pattern, where rhythmicity is lost during BDL but restored by CD36 deletion, and the "N-R-N" pattern, where abnormal rhythms induced by BDL are normalized by CD36 deficiency.
Mechanistically, CD36 regulated the rhythmic activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and cholesterol 7α-hydroxylase (CYP7A1), two critical enzymes controlling cholesterol and bile acid synthesis. CD36 deficiency reversed abnormal HMGCR/CYP7A1 oscillations induced by cholestatic injury, thereby restoring bile acid homeostasis and reducing toxic bile acid accumulation.

Furthermore, targeted suppression of CD36 using lipid nanoparticle-delivered siRNA effectively alleviated liver injury and restored bile acid rhythmicity in vivo, highlighting the therapeutic potential of CD36 inhibition.

Overall, this study identifies CD36 as a key regulator linking circadian rhythm disruption to cholestatic liver injury through the HMGCR/CYP7A1 axis, providing important insights into the interplay between circadian biology and liver disease while highlighting CD36 as a promising therapeutic target for cholestatic disorders.

Reference
Title of the original paper: Elevated diurnal CD36 expression disrupts the bile acid synthesis rhythm leading to cholestatic liver injury and inflammation via the HMGCR/CYP7A1 axis

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101776

Funding Information:
National Natural Science Foundation of China (No. 32030054, 82170586, U23A20415, 32400943)
National Key R&D Program of China (No. 2022YFC2502500)
Science and Technology Research Program of Chongqing Municipal Education Commission (No. KJZD-K202200402, CSTB2023NSCQ-LZX0001)
Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University and Program for Youth Innovation in Future Medicine of Chongqing Medical University (No. W0163)
Postdoctoral Foundation of Chongqing Natural Science Foundation (No. TB2023NSCQ-BHX0145)
Joint Project of Pinnacle Disciplinary Group of the Second Affiliated Hospital of Chongqing Medical University

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4 | Impact Factor: 9.4

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Print ISSN: 2352-4820
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(A) Experimental approach for establishing the animal model. The figure was created via BioRender.com. (B) Hepatic levels of TC, FC, PL, CE, BA, and FFA in the SHAM and BDL mice at ZT0 and ZT12. (C) Serum levels of ALP, GGT, ALT, AST, TBA, and C4 in the SHAM and BDL mice at ZT0 and ZT12. (D) mRNA expression levels of core clock genes in the livers of SHAM and BDL mice over a 24-h period. (E) mRNA expression levels of key genes involved in bile acid synthesis, regulation, and secretion in the livers of SHAM and BDL mice over 24 h (n = 4 per time point per group). The data were shown as mean ± SEM. Group comparisons were performed via two-way ANOVA. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 versus the control groups; #p < 0.05, ##p < 0.01, and ###p < 0.001 for ZT0 versus ZT12 within the same group. ZT0 refers to the beginning of the subjective circadian period (6:00 a.m.). The black bar represents the dark phase from 6:00 p.m. to 6:00 a.m. TC, total cholesterol; FC, free cholesterol; PL, phospholipid; BA, bile acid; CE, cholesteryl ester; FFA, free fatty acid; BDL, bile duct ligation; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; C4, 7α-hydroxy-4-cholesten-3-one; TBA, total bile acids.
(A) mRNA expression levels of core clock genes in the livers of SHAM, BDL and BDL + LKO mice at ZT0 and ZT12. (B) mRNA expression levels of key genes involved in bile acid synthesis, regulation, and cholesterol synthesis in the livers of SHAM, BDL, and BDL + LKO mice at ZT0 and ZT12. (C) Protein expression levels of HMGCR and CYP7A1 in liver tissues of SHAM, BDL, and BDL + LKO mice at ZT0 and ZT12, as determined by Western blotting analyses. (D) Schematic representation of CD36-reprogrammed genes and pathways. n = 4 per time point per group. The data were presented as mean ± SEM. Group comparisons were conducted via two-way ANOVA. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 versus the control group; ns, not significant. ZT0 marks the beginning of the subjective circadian period (6:00 a.m.). HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; CYP7A1, cholesterol 7α-hydroxylase; CD36, cluster of differentiation 36; BDL, bile duct ligation.
(A) Experimental approach for establishing the animal model. The figure was created via BioRender.com. (B) Representative images of liver and gallbladder tissues from the SHAM, BDL, and BDL + LKO mice at ZT0 and ZT12. Scale bar: 1 cm. (C) Liver weights of the different groups. (D) Liver weight-to-body weight ratios of the different groups. (E) Hepatic levels of TC, FC, CE, PL, FFA, and BA in the SHAM, BDL and BDL + LKO mice at ZT0 and ZT12. (F) Serum levels of C4 and TBA in the SHAM, BDL and BDL + LKO mice at ZT0 and ZT12. (G) Hepatic mRNA levels of the indicated genes. (H) Representative images of liver tissue from SHAM, BDL and BDL + LKO mice subjected to hematoxylin-eosin, Sirius red, and immunohistochemistry staining for F4/80 and CK19. Scale bars: 100 or 200 μm. n = 4 per time point per group. The data were presented as mean ± SEM. Group comparisons were conducted via two-way ANOVA. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 versus the control group; ns, not significant. ZT0 marks the beginning of the subjective circadian period (6:00 a.m.). CD36, cluster of differentiation 36; BDL, bile duct ligation; TC, total cholesterol; FC, free cholesterol; PL, phospholipid; BA, bile acid; CE, cholesteryl ester; FFA, free fatty acid; C4, 7α-hydroxy-4-cholesten-3-one; TBA, total bile acids.

29/06/2026 Compuscript Ltd

Regions: Europe, Ireland, Asia, China

Keywords: Science, Life Sciences

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