ERMP1 Increases NAFLD Severity by Increasing Mitochondrial Bioenergetics

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a condition where there is a buildup of fat in the liver cells that is not caused by alcohol use. It is estimated that 20-30% of the population worldwide are affected by NAFLD but to this day, there are no current treatment options. Previous studies in our lab have shown “key driver” genes regulating NAFLD. Follow-up studies have shown mitochondrial dysfunction as a key mechanistic driver of NAFLD and have identified Endoplasmic Reticulum Metallopeptidase 1 (ERMP1) as a candidate gene. ERMP1 is a zinc-binding protease and is highly expressed in several cancers. We found that Ermp1 expression was positively associated with NAFLD progression and hepatic TG accumulation using liver transcriptome from ~100 different mouse strains called hybrid mouse diversity panel (HMDP). Follow-up network enrichment analysis revealed mitochondrial, endoplasmic reticulum, cell cycle, and circadian rhythm enrichments, as well as liver-related disease traits including fatty liver disease, steatohepatitis, liver cirrhosis and neoplasms. Unfortunately, there still isn’t a complete understanding of factors governing the progression of NAFLD, or the effect ERMP1 gene has on the liver. But since mitochondrial dysfunction has been shown to play a causal role in liver fat buildup during NAFLD, we started our investigation here. We hypothesize that there is a direct relationship between NAFLD severity and ERMP1 gene, which is mediated by enhanced mitochondrial activity. We found that when downregulating the ERMP1 gene, there was a reduction in mitochondrial respiration under lipid stress conditions in a mouse liver cell line (AML12). The same was also seen when decreasing the expression of ERMP1 in a diet-induced obesity model. This was accompanied by reduced mitochondrial OXPHOS subunits, specifically Complex II. Taken together, we conclude that ERMP1 increases NAFLD severity by increasing mitochondrial activity. R00DK120875. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.