CD36 promotes cholesterol gallstone formation by regulating cholesterol metabolism via SREBP2.

Abstract

BACKGROUND: Cholecystitis is a common biliary disorder, and cholesterol gallstones are a major underlying cause closely associated with disturbed cholesterol metabolism. However, the role of CD36, a multifunctional scavenger receptor, in cholesterol gallstone formation remains unclear. METHODS: Plasma proteomics was performed in patients with cholecystitis without gallstones (CC, n = 9) and cholesterol gallstones (GS, n = 63). CD36 levels in serum and bile were validated by ELISA and correlated with biliary lipid composition. In vivo, hepatocyte-enriched CD36 overexpression was induced by AAV8-TBG in lithogenic diet-fed mice, followed by assessment of gallstone formation, biliary crystal/sludge formation, gallbladder histology, serum and biliary lipid profiles, and cholesterol saturation index. In vitro, CD36 was overexpressed or knocked down in primary hepatocytes and HepG2 cells, and cholesterol secretion, protein expression, SREBP2 nuclear translocation, CD36-SREBP2 interaction, and rescue effects were analyzed using biochemical assays, Western blotting, co-immunoprecipitation, and re-expression/silencing experiments. RESULTS: CD36 was significantly upregulated in the plasma of patients with cholesterol gallstones and was further confirmed to be elevated in both serum and bile. Biliary CD36 levels correlated positively with biliary cholesterol and negatively with bile acid levels. In mice, hepatic CD36 overexpression exacerbated gallstone formation, increased serum lipids, elevated biliary cholesterol and cholesterol saturation index, and aggravated gallbladder injury. CD36 also increased hepatic expression of HMGCR, SREBP2, and PCSK9. In hepatocytes, CD36 promoted cholesterol secretion and upregulated these cholesterol metabolic regulators. Mechanistically, CD36 interacted with SREBP2 and enhanced its nuclear translocation. CONCLUSION: CD36 promotes cholesterol gallstone formation by enhancing SREBP2-dependent cholesterol metabolic dysregulation and may represent a potential therapeutic target for cholesterol gallstone disease.

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