PT  - JOURNAL ARTICLE
AU  - Rong Li
AU  - Wenqiang Zhu
AU  - Piaopiao Huang
AU  - Yang Yang
AU  - Fei Luo
AU  - Wen Dai
AU  - Li Shen
AU  - Wenjing Pei
AU  - Xiansheng Huang
TI  - Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway
AID  - 10.1101/2021.03.02.433415
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.02.433415
4099  - http://biorxiv.org/content/early/2021/03/02/2021.03.02.433415.short
4100  - http://biorxiv.org/content/early/2021/03/02/2021.03.02.433415.full
AB  - The antipsychotic drug olanzapine was reported to induce nonalcoholic fatty liver disease (NAFLD), whereas the underlying mechanism remains incompletely understood. This study investigated whether apolipoprotein A5 (apoA5) and sortilin, two interactive factors involved in NAFLD pathogenesis, are implicated in olanzapine-induced NAFLD. In the present study, at week 8, olanzapine treatment successfully induced hepatic steatosis in male C57 BL/6J mice, even when fed a normal chow diet, which was independent of animal body weight gain. Likewise, olanzapine effectively mediated hepatocyte steatosis in human HepG2 cells in vitro, characterized by substantially elevated intracellular lipid droplets. Increased plasma triglyceride concentration and decreased plasma apoA5 levels were observed in mice treated for 8 weeks with olanzapine. Surprisingly, olanzapine markedly enhanced hepatic apoA5 protein levels in mice, without a significant effect on rodent hepatic ApoA5 mRNA expression. Our in vitro study showed that olanzapine reduced apoA5 protein levels in the medium and enhanced apoA5 protein expression in hepatocytes, whereas this drug exerted no effect on hepatocyte APOA5 mRNA expression. By transfecting APOA5 siRNA into HepG2 cells, it was demonstrated that APOA5 knockdown effectively reversed olanzapine-induced hepatocyte steatosis. In addition, olanzapine drastically increased sortilin mRNA and protein levels in vivo and in vitro. Interestingly, SORT1 knockdown reduced intracellular apoA5 protein expression and increased medium apoA5 protein levels in vitro, without affecting intracellular APOA5 mRNA expression. Furthermore, SORT1 knockdown greatly ameliorated hepatocyte steatosis in vitro. This study provides the first evidence that sortilin inhibits the hepatic apoA5 secretion that is attributable to olanzapine-induced NAFLD, which provides new insight into effective strategies against NAFLD for patients with schizophrenia administered olanzapine.Competing Interest StatementThe authors have declared no competing interest.ALTalanine transaminaseApoA5apolipoprotein A5ASTaspartate aminotransferaseDMSOdimethyl sulfoxideH&Ehematoxylin and eosinHDL-Chigh-density lipoprotein cholesterolLDL-Clow-density lipoprotein cholesterolNAFLDnonalcoholic fatty liver diseaseOROOil Red O