Hepatocyte-specific knockout of YAP protects against atherosclerosis via inhibition of ANGPTL3 in mice

Background and Aims Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular disease (ASCVD). Although some lipid-lowering drugs have demonstrated positive effects in patients with ASCVD, their effects are limited in those with homozygous familial hypercholesterolemia (HoFH). It is essential to seek new lipid-lowering targets. Yes-associated protein (YAP) may be involved in lipid metabolism in liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Methods Hyperlipidemia models were generated in apoE-/- mice or mice injected with AAV8-D377Y-mPCSK9, which degrades and deletes low density lipoprotein receptor (LDLR), by being fed a high cholesterol diet (HCD) for 12 weeks. We measured the expression level of hepatic YAP in these apoE-/- mice. Next, we created YAPΔHep apoE-/- mice to further determine the role of YAP in hyperlipidemia and atherosclerosis. AML12 cells and mice injected with AAV8-D377Y-mPCSK9 or YAPΔHepapoE-/- mice were used to elucidate its mechanism. Finally, apoE-/- or LDLR-/- mice were used to observe the therapeutic efficacy of AAV8-Alb-shYAP for hyperlipidemia and atherosclerosis. Results HCD-fed apoE-/- mice showed increased levels of YAP in the liver. Further investigation indicated that YAPΔHepapoE-/- mice exhibited lighter hyperlipidemia and atherosclerosis than YAPflox/floxapoE-/- mice fed with HCD. Conversely, hepatocyte-specific overexpression of YAP (5S) deteriorated hyperlipidemia and atherosclerosis in HCD-fed apoE-/- mice. Furthermore, the lipid-lowering effect of YAP deficiency in hepatocytes was independent of LDLR. Hepatocyte-specific overexpression of angiopoietin-like-3 (ANGPTL3) aggravated hyperlipidemia and atherosclerosis in YAPΔHepapoE-/- mice, indicating that ANGPTL3 is responsible for the function of YAP in hyperlipidemia. Mechanistically, YAP upregulated ANGPTL3 via TEAD4 in hepatocytes independent of LDLR. Notably, AAV8-Alb-shYAP lowered lipid levels in apoE-/- or LDLR-/- mice. Conclusion Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for HoFH.