Depletion of Hepatic SREBP2 Protects Against Hypercholesterolemia and Atherosclerosis through the ANGPTL3‐LPL Axis

Abstract Lipolysis of triglyceride‐rich lipoproteins by peripheral lipoprotein lipase (LPL) plays an essential role in maintaining systemic cholesterol/lipid homeostasis. Human genetic studies have unequivocally demonstrated that activation of LPL pathway reduces risks for both coronary artery disease (CAD) and type 2 diabetes (T2D). Although sterol regulatory element‐binding protein 2 (SREBP2) is well established as the master transcription factor that regulates the hepatic biosynthesis of both cholesterol and fatty acids, whether and how its activity in liver interacts with peripheral LPL pathway remains unknown. Here, it is demonstrated that acute liver‐specific depletion of SREBP2 results in divergent effects on the regulation of peripheral LPL activity in mice, depending on the presence or absence of low‐density lipoprotein receptors (LDLR). SREBP2 deficiency drastically elevates peripheral LPL activity through downregulation of plasma angiopoietin‐related protein 3 (ANGPTL3) levels in LDLR‐deficient mice. Moreover, in addition to SREBP2's transcriptional regulation of ANGPTL3, it is found that SREBP2 promotes proteasome‐based degradation of ANGPTL3 in the presence of LDLR. Remarkably, acute depletion of hepatic SREBP2 protects against hypercholesterolemia and atherosclerosis, in which atherosclerotic lesions are reduced by 45% compared to control littermates. Taken together, these findings outline a liver‐peripheral crosstalk mediated by SREBP2‐ANGPTL3‐LPL axis and suggest that SREBP2 inhibition can be an effective strategy to tackle homozygous familial hypercholesterolemia (HoFH).