Hepatic HuR protects against atherosclerosis through bile acid production

Hepatocyte-specific HuR knockout mice exhibit a lean MAFLD (metabolic-associated fatty liver disease)-like phenotype in response to high-fat diet. However, if this phenotype further impacts the development of atherosclerosis (AS) remains to be studied. Here, we report that HuR represses the production of chenodeoxycholic acid (CDCA) and taurocholic acid (TCA) in the liver through repressing the expression of CYP7A1, the rate-limiting enzyme for the central pathway of BA production. HuR destabilizes Cyp7a1 mRNA by associating with its 3’UTR. In response to high-cholesterol diet (HCD), hepatic HuR increases the expression of CYP7A1 in the liver, thereby increasing the levels of CDCA and TCA in the liver and serum, activating HuR-PSPF (platelet-secreted pro-inflammatory factors) regulatory process, and aggravating HCD-induced AS in APOE (-/-) mice. Administration of TCA and CDCA activates HuR-PSPF regulatory process and at the same time aggravates HCD-induced AS. Platelet HuR ablation mitigates the effect of hepatic HuR ablation in aggravating HCD-induced AS. In the liver tissues from patients with lean MAFLD, the reduction of HuR expression, the induction of CYP7A1 expression and the activation of HuR-PFPF regulatory process, are concurrently observed. Our findings suggest an important role of hepatic HuR-CYP7A1 regulatory process in the development of AS in lean MAFLD-like lipid dysregulation.