Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis [Lpcat3_OE]

Nonalcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis, is emerging as a leading etiology of hepatocellular carcinoma (HCC). However, the mechanisms underlying the pathogenesis of NASH are not well understood. Here, we show that membrane phospholipid (PL) composition determined by a remodeling process modulates the progression of NASH. The expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a PL remodeling enzyme that produces polyunsaturated PLs, is dramatically suppressed in human NASH livers compared to controls. LPCAT3 expression is inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes the development of both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency increases reactive oxygen species production, likely due to impaired mitochondrial homeostasis as demonstrated by reduced mitochondrial DNA content and fragmented mitochondrial morphology. Overexpressing Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH. These results suggest that manipulating LPCAT3 expression may be an effective therapeutic strategy for NASH. Overall design: C57BL/6 mice were fed with NASH diet for 7 weeks and were injected AAV-TBG-eGFP as control (eGFP) or AAV-TBG-Lpcat3 (Lpcat3) for overexpression of Lpcat3 specifically in the liver. Both groups of mice were further fed with NASH diet for 9 weeks. Then, total liver RNA were isolated for RNA sequencing.