Objective-
Dyslipidemia is one of the key factors behind
coronary heart disease. Blood and lymphatic vessels play pivotal roles in both
lipoprotein metabolism and development of
atherosclerotic plaques. Recent studies have linked members of
VEGF (
vascular endothelial growth factor) family to lipid metabolism, but the function of
VEGF-D has remained unexplored. Here, we investigated how the deletion of
VEGF-D affects
lipid and
lipoprotein metabolism in atherogenic LDLR-/- ApoB100/100 mice. Approach and Results- Deletion of
VEGF-D (
VEGF-D-/-LDLR-/-ApoB100/100) led to markedly elevated plasma
cholesterol and
triglyceride levels without an increase in
atherogenesis. Size distribution and hepatic
lipid uptake studies confirmed a delayed clearance of large
chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of
VEGF-D signaling significantly decreased the hepatic expression of SDC1 (
syndecan 1), which is one of the main receptors for
chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in
VEGF-D deficient mice. Furthermore, hepatic
RNA-sequencing revealed that
VEGF-D is also an important regulator of genes related to lipid metabolism and
inflammation. The lack of
VEGF-D signaling via VEGFR3 (
VEGF receptor 3) led to lowered expression of genes regulating
triglyceride and
cholesterol production, as well as downregulation of peroxisomal β-oxidation pathway. Conclusions- These results demonstrate that
VEGF-D, a powerful lymphangiogenic and angiogenic
growth factor, is also a major regulator of
chylomicron metabolism in mice.