Affiliation:
1. The Second Xiangya Hospital of Central South University Department of Cardiovascular Medicine
2. The Second Xiangya Hospital of Central South University
3. zhongnan daxue xiangya er yiyuan: The Second Xiangya Hospital of Central South University
Abstract
Abstract
Background Long-term olanzapine treatment reportedly induces nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) degrades low-density lipoprotein receptor (LDLR) and is involved in NAFLD pathogenesis via unknown mechanisms. Here, we investigated the role and mechanism of PCSK9 in olanzapine-induced NAFLD.METHODS The mice model of olanzapien drives NAFLD was developed to investigate the role and molecular mechanism of PCSK9 in terms of hepatic cholesterol homeostasis and triglyceride metabolism in vivo. In vitro, rhPCSK9 protein and transient transfection of plasmid (SREBP1c and PCSK9 overexpression) and siRNA (SREBP1c siRNA, PCSK9 siRNA) were used to probe the specific molecular mechanism of PCSK9 in olanzapine-induced hepatic steatosis. The mRNA and protein exprssion of lipid-related genes were detected by RT-qPCR and western blotting, respectively, and protein expression in liver sections and cell lines was investigated using immunofluorescence.RESULTS Olanzapine increased PCSK9 expression by upregulating sterol regulatory element-binding protein 1c (SREBP-1c), which upregulated NCP1L1 promoting hepatocyte cholesterol intake. Olanzapine-mediated PCSK9 upregulation also increased the mRNA expression of factors involved in hepatic lipid synthesis (FAS, SCD1, and ACL), lipid uptake (FATP1), and cholesterol synthesis (HMGCR, HMGCS, and CYP51A1) but decreased that of factors involved in lipid oxidation (SCAD and PPARα), both of which contribute toward hepatic steatosis.CONCLUSION Our study, for the first, systematically analyzed the role of PCSK9 in olanzapine-induced NAFLD via both receptor-dependent and -independent mechanisms. We revealed that olanzapine enhances hepatic SREBP-1c expression, thereby increasing PCSK9 levels. This upregulates NPC1L1 and the expression of genes related to lipid metabolism, particularly those related to de novo lipogenesis and cholesterol biosynthesis. Thus, PCSK9 could serve as a target for the development of NAFLD therapies in olanzapine-treated patients with schizophrenia. Moreover, our findings suggest that PCSK9 inhibitors may have additional clinical benefits beyond treating cardiovascular diseases. Nonetheless, our study has several limitations, such as the lack of PCSK9-knockout mice, which could be conducive to unraveling the exact mechanisms underlying PCSK9-mediated effects on NPC1L1 and genes related to lipid metabolism, which require further investigation.
Publisher
Research Square Platform LLC