Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein

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 into 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. • Plasmalemma vesicle-associated protein (PLVAP) has functions beyond the endothelium • Hepatic stellate cell (HSC) PLVAP is required for fasting liver lipid utilization • HSCs regulate fasting liver insulin signaling and energy substrate preference • HSCs modulate whole-body lipid partitioning and glucose tolerance Hansen et al. show that the hepatic stellate cell-expressed plasmalemma vesicle-associated protein is required for the normal switch from carbohydrate to lipid utilization during fasting. This reveals a novel layer of metabolic regulation imposed by perivascular cells of the liver, with possible implications for whole-body metabolism.