The liver is a central hub for metabolism. Metabolic adaptation in hepatocytes during fasting is therefore essential for homeostasis. In the liver, HSCs envelop the microvasculature where they are known to sense hormones and regulate blood flow. Selective knockout of the Plvap gene in HSCs, now elucidates a hitherto unknown role for HSCs in liver metabolism. Livers in knockout mice presented clear changes in their metabolic gene programs and were unable to utilize fatty acids during fasting. Lipidomics analysis and fatty acid tracing in live mice supported disruption of fatty acid uptake and retention. Instead, fasted knockout mice showed elevated liver insulin signaling, improved glucose tolerance, and rerouting of fatty acids to skeletal muscle.
“This study clearly demonstrate that HSCs have important functions beyond vitamin-A storage and liver hemodynamics. As liver pericytes, they seem to communicate with hepatocytes to regulate liver insulin signaling and thereby take active part in the regulation of liver homeostasis” says Daniel Hansen, Postdoc in the Ravnskjaer Lab, and first-author on the study.
PLVAP protein is known as endothelium-specific, however, the researchers have now discovered its expression and importance in pericyte-like HSCs. During fasting, non-esterified fatty acids are released by lipolysis in the adipose tissue and taken up by the liver for oxidative metabolism and ketogenesis. This study shows that the process is more regulated than we imagined, and that HSCs are important regulators. If conserved in humans, the translational implications of this system are very interesting adds ATLAS PI and corresponding author Kim Ravnskjaer: “These mice not only show us a new way to control fat metabolism but also appear to have better insulin sensitivity and glucose control. Central aspects in the management of obesity, type-2 diabetes, and their complications”.
The study was conducted by the Ravnskjaer Lab in collaboration with scientists at University of Southern Denmark, University of Turku (FI), Columbia University (US), and Kanazawa University (JP).
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The study is published in Cell Metabolism and the abstract and link to full text version can be found .
Correspondence may be directed to Associated Professor and ATLAS partner Kim Ravnskjaer.