Plasmalemma vesicle-associated protein in hepatic stellate cells is a central regulator of hepatic fatty acid utilization

The liver is essential for fatty acid utilization during fasting. Fatty acids released by lipolysis from adipose tissue during fasting are taken up from the blood by hepatocytes and esterified as triacylglycerols for oxidative metabolization and ketogenesis. Whereas the regulation of fatty acid oxidation in hepatocytes is well understood, transport of non-esterified fatty acids (NEFAs) from the liver sinusoidal lumen to the hepatocyte is not. Here, we show that murine hepatic stellate cells (HSCs), enveloping the liver sinusoids as pericytes, and their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control hepatic NEFA uptake during fasting. HSC-specific ablation of PLVAP suppresses hepatocyte fatty acid esterification to di- and triacylglycerols along with fasting fatty acid utilization and ketogenesis. Consistently, single cell-resolved transcriptomics further revealed severe perturbation of hepatocyte gene programs governing normal fatty acid handling, oxidation, and ketogenesis. By super-resolution microscopy we localized HSC PLVAP to caveolae residing along the sinusoidal lumen strongly supporting a role for PLVAP in caveolar transcytosis of NEFAs across HSCs and hence the sinusoid wall as rate-limiting for hepatic fatty acid utilization during fasting. This was supported by a similar decline in neutral lipid droplet formation in livers of fasting Caveolin-1 knockout mice. Altogether, our study shows vital roles for PLVAP and for HSCs in normal fasting metabolism of liver.