Liver-specific knockdown of long-chain acyl-CoA synthetase 4 reveals its key role in VLDL-TG metabolism and phospholipid synthesis in mice fed a high-fat diet

Long-chain acyl-CoA synthetase 4 (ACSL4) has a unique substrate specificity for arachidonic acid (AA). Hepatic ACSL4 is coregulated with the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (LPCAT3) by PPARd to modulate plasma triglyceride metabolism. In this study, we investigated the acute effects of hepatic ACSL4 deficiency on lipid metabolism in adult mice fed a high-fat diet (HFD). Adenovirus-mediated expression of a mouse ACSL4 shRNA (Ad-shAcsl4) in the liver of HFD-fed mice led to a 43% reduction of hepatic arachidonoyl-CoA synthetase activity and a 53% decrease in ACSL4 protein levels as compared to mice receiving control adenovirus (Ad-shLacZ). Attenuated ACSL4 expression resulted in a substantial decrease in circulating VLDL-triglyceride levels without affecting plasma cholesterol. Lipidomics profiling revealed that knocking down ACSL4 altered liver phospholipid compositions, with the greatest impact on accumulation of abundant Lyso PC species LPC (16:0) and LPC (18:0), a...