Elevated diurnal CD36 expression disrupts the bile acid synthesis rhythm leading to cholestatic liver injury and inflammation via the HMGCR/CYP7A1 axis

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are characterized by disrupted bile acid (BA) homeostasis and subsequent liver injury. Emerging evidence indicates that circadian rhythms significantly influence liver metabolism and the pathogenesis of liver diseases. CD36 has been identified as a regulator of the hepatic circadian clock and metabolic processes; however, the specific mechanisms by which CD36 links circadian rhythms to cholestatic liver disease remain unclear. In this study, we employed bile duct ligation (BDL) mice and liver-specific CD36 knockout (CD36 LKO) mice to examine the role of CD36 in BA metabolism and circadian gene expression. BDL mice presented disrupted rhythms in both liver clock and BA metabolism, accompanied by increased diurnal expression of CD36. Conversely, in the context of BDL, CD36 LKO reduced cholestatic liver injury, improved BA metabolism, and restored diurnal variation of BA levels. Transcriptomic analysis revealed that BA metabolism genes were regulated by CD36, particularly those involved in synthesis, which displayed diurnal variation. Targeted inhibition of CD36 expression effectively mitigated liver injury and inflammation in BDL mice by restoring the rhythmicity of HMGCR/CYP7A1 and normalizing the BA pool size. These findings suggest that CD36 plays a pro-cholestatic role through its regulation of rhythmic BA synthesis and that its inhibition may represent a promising therapeutic strategy for cholestatic liver diseases.