Olfactomedin 4 deletion exacerbates nonalcoholic fatty liver disease through P62-dependent mitophagy in mice

Background & aims: Olfactomedin 4 (OLFM4) is a glycoprotein that is related to obesity and insulin resistance. This study aims to investigate the role and mechanisms of OLFM4 in nonalcoholic fatty liver disease (NAFLD). Approach & results: OLFM4 expression levels were significantly increased in liver samples from NAFLD patients and in cellular and mouse models of NAFLD. Cell lines deficient in or overexpressing OLFM4 and Olfm4-/-mice were established to study its role in NAFLD. OLFM4 deficiency significantly aggravated diet-induced hepatic steatosis and inflammation, while re-expression of OLFM4 ameliorated diet-induced hepatic steatosis and inflammation in mice. Mechanistically, OLFM4 deficiency disrupted mitochondrial structure and decreased mitophagy in hepatocytes, thereby aggravating hepatic lipogenesis, inflammation, and insulin resistance. Moreover, OLFM4 directly interacted with P62, and OLFM4 deficiency decreased mitophagy in both cellular and mouse models of NAFLD through a P62-dependent mechanism. We also show that blocking the P62-ZZ-domain using XRK3F2 prevented diet-induced NAFLD in Olfm4-/- mice.Conclusion: OLFM4 is significantly upregulated in NAFLD, and OLFM4 deletion exacerbates NAFLD through P62 dependent mitophagy.