Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein [bulk RNA-seq]
The liver is essential for normal fatty acid utilization during fasting. Circulating fatty acids are taken up by hepatocytes and esterified as triacylglycerols for either oxidative metabolization and ketogenesis or export. Whereas the regulation of fatty acid oxidation in hepatocytes is well understood, the uptake and retention of non-esterified fatty acids by hepatocytes is not. Here, we show that murine hepatic stellate cells (HSCs) and their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control hepatic substrate preference for fasting energy metabolism. HSC-specific ablation of PLVAP in mice elevated hepatic insulin signaling and improved glucose tolerance. Fasted HSC PLVAP knockout mice showed suppressed hepatic fatty acid esterification to di- and triacylglycerols shifting fasting metabolism from fatty acid oxidation to reliance on carbohydrates. By super-resolution microscopy we localized HSC PLVAP to caveolae residing along the sinusoidal lumen supporting a role for HSCs and PLVAP-diaphragmed caveolae in normal fasting metabolism of the liver. Overall design: Bulk RNA-sequencing from fasted or refed HSC-Plvap-knockout mice, Cav1-knockout mice, and control mice Bulk RNA-sequencing from over-night fasted HSC-Plvap-knockout and control mice given six weeks of either western diet or high-fat diet