Hepatocyte-specific SLC27A4 deletion ameliorates nonalcoholic fatty liver disease in mice via suppression of phosphatidylcholine-mediated PXR activation

The protein Solute carrier family 27 member 4 (SLC27A4) is crucial for fatty acid synthesis and β-oxidation, but its role in hepatic steatosis and nonalcoholic fatty liver disease (NAFLD) progression is not fully understood. Mice with AAV-mediated overexpression of Slc27a4 in liver and hepatocytes-specific deletion of Slc27a4 were fed a standard chow diet, a high-fat diet (HFD), or a methionine and choline-deficient diet (MCD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, lipidomic analysis, RNA-seq analysis, qPCR, western blot and immunofluorescence. This study found elevated expression of SLC27A4 in individuals with NAFLD and OAPA-treated MPHs cells, leading to increased lipid accumulation and diet-induced liver steatosis, inflammation, and fibrosis. Conversely, hepatocyte-specific deletion of Slc27a4 improved the development of both NAFLD and NASH. SLC27A4 overexpression resulted in increased hepatic pregnane X receptor (PXR) expression and accumulation of phosphatidylcholine (PC), which activates PXR signaling and inducing SLC27A4 expression. PXR overexpression hinders the protective impact of Slc27a4 deletion on lipid accumulation and inflammation, whereas its deficiency in mice reduces the effect of Slc27a4 overexpression on NAFLD development. These results indicate that SLC27A4 plays a critical role of lipid accumulation and inflammation, and is implicated in the development of NAFLD progression, rendering it potentially actionable target for NAFLD treatment. The activation of PXR by SLC27A4 overexpression-mediated PC (19:1_18:2) accumulation may transcriptionally upregulate the expression of SLC27A4, thereafter inducing its ectopic overexpression in the liver, and subsequently causing transport of excessive hepatic PC from peripheral tissues to liver and accelerating NAFLD development. [Display omitted] •SLC27A4 expression is enhanced in liver of patients with NAFLD, and NAFLD or NASH mice model.•SLC27A4 overexpression elevates hepatic PC(19:1_18:2) accumulation, and activates PXR signaling.•PXR transcriptionally regulated SLC27A4 expression through physical binding to its promoter.•PXR overexpression impairs the protective effect of SLC27A4 deletion in lipid accumulation and inflammation.•PXR deficiency reverses SLC27A4 overexpression-mediated the NAFLD development.