Role of platelet-derived growth factor B in cholesterol and glucose metabolism

Abstract

Platelet-derived growth factor (PDGFB) is a critical molecule for recruiting pericytes. Due to the fundamental role of the pericytes in angiogenesis and vascular stability, PDGFB knockout mice die perinatally from severe hemorrhage and edema. PDGFB retention motif knockout mouse (Pdgfbret/ret) is one of the available models to study the postnatal effect of PDGFB signaling. My PhD projects intensively used Pdgfbret/ret to explore the role of PDGFB in cholesterol and glucose metabolism.

In the brain, the pericyte coverage on the blood-brain barrier (BBB) of Pdgfbret/ret is reduced by 70%, which leads to increased permeability to a series of high- and low-mass tracers. Physiologically cholesterol metabolism in the brain is isolated from the other organs or the circulation by BBB. Paper I and II used Pdgfbret/ret mice as a BBB leakage model and studied the metabolic changes of cholesterol metabolism in the brain when BBB lose its integrity. Our results show that in Pdgfbret/ret, more plant sterols are accumulated in the brain due to increased influx. Meanwhile due to increased efflux of 24(S)-hydroxycholesterol, the negative feedbacks to de novo biosynthesis of cholesterol in the brain is diminished.

Liver has been considered as a special organ for PDGFB signaling, because recruitment of the hepatic stellate cells (HSCs), also disputably known as the liver pericytes, are recruited independently of PDGFB. PDGFB is known to be expressed from the endothelial cells of portal veins, but its physiological role is still poorly investigated. In Paper III, we describe for the first time that cholangiocytes, the epithelial cells of bile ducts, are also expressing PDGFB. Similar to pericyte deficiency on BBB, Pdgfbret/ret mice show deficiency of periductal mesenchymal cells, together with bile duct dilation and portal inflammatory infiltrate (PII). PII is of great clinical importance, because it is an early marker ubiquitously present in many biliary and non-biliary liver diseases. Using Pdgfbret/ret, together with PDGFB knockouts and Sox2-Cre;PDGFRβ+/D849V mutants in which PDGFRβ is over-active, we confirmed that elevated PDGFB signaling leads to PII directly. In Pdgfbret/ret, PII is accompanied by a lopsided immune profile, with increased CD8 T cells and decreased NKT cells, which mimics the immune profile at the steatosis stage of non-alchoholic fatty liver diseases. From metabolic perspective, we show that immune response in Pdgfbret/ret leads further to intolerance to high cholesterol diet and susceptibility to hepatic steatosis by suppressing VLDL secretion.

Paper IV focuses on the function of PDGFB in pancreatic islets. We show that PDGFB is not a key factor to maintain the pericyte coverage in pancreatic islets. In Pdgfbret/ret, the slightly disrupted PDGFB signaling is not enough to affect vascular functions in pancreatic islets. The first phase of insulin secretion in Pdgfbret/ret is earlier and stronger, and our current data indicates a systematic factor as the underlying mechanism.