Dataset Information

HELZ2 regulates APOB mRNA stability to modulate fatty liver disease and atherosclerosis

ABSTRACT: Background: Apolipoprotein B (APOB) is essential for lipoprotein assembly and secretion and plays a central role in the development of cardiovascular disease and metabolic dysfunction-associated steatotic liver disease (MASLD). While APOB protein degradation during very low-density lipoprotein (VLDL) maturation has been extensively studied, the regulation of APOB mRNA stability under physiological and pathological conditions remains unexplored. Methods: A forward genetic screen in randomly mutagenized mice identified helicase with zinc finger 2 (HELZ2) as a critical regulator of lipid metabolism. The metabolic effects of HELZ2 mutations or deficiency were evaluated in mice maintained on a chow diet or a high-fat diet (HFD). We also employed a doxycycline-inducible, liver-specific HELZ2 overexpression model to test the sufficiency of hepatocyte Helz2 upregulation. Biochemical assays were used to assess HELZ2 binding to APOB mRNA and its role in APOB mRNA degradation, while the effect of HELZ2 modulation on atherosclerosis was examined in Apoe-/- and Ldlr-/- mouse models. Results: We discovered a unique gain-of-function mutation in HELZ2 (L1833P, termed Colby) that promotes hepatic lipid accumulation independently of changes in body weight on a standard chow diet. Mechanistically, HELZ2 binds APOB mRNA and degrades it via its helicase activity, ensuring tight control of hepatic APOB levels. The Colby mutation enhances HELZ2 helicase activity, resulting in marked reductions in Apob expression and increased hepatic lipid accumulation. Conversely, Helz2-deficient mice show increased Apob mRNA levels and reduced hepatic triglycerides on a HFD. Notably, modest liver-restricted induction of HELZ2 was sufficient to decrease hepatic Apob mRNA and alter lipid handling, phenocopying the Helz2Colby state and supporting the gain-of-function mechanism. A single copy of the Helz2Colby mutation confers protection against atherosclerosis in Apoe-/- and Ldlr-/- mice. Conclusions: HELZ2 is a key regulator of APOB mRNA stability and lipid metabolism. Genetic or pharmacological modulation of HELZ2 activity represents a promising therapeutic strategy for cardiovascular disease and MASLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE309603 | GEO | 2026/01/21

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description: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.

Project description:Background: The low-density lipoprotein receptor (LDLR) in the liver plays a crucial role in clearing low-density lipoprotein cholesterol (LDL-C) from the bloodstream. This process takes place mainly in the liver. Under atherogenic conditions, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), secreted by the liver, binds to LDLR on hepatocytes, preventing its recycling and enhancing its lysosomal degradation. This process reduces LDL-C clearance, promoting hypercholesterolemia. Epsins, a family of ubiquitin-binding endocytic adaptors, are key regulators of atherogenesis in lesional cells, including endothelial cells and macrophages. Given epsins' canonical role in regulating endocytosis of cell surface receptors, we aimed to determine whether and how liver epsins contribute to PCSK9-mediated LDLR endocytosis and degradation, thereby impairing LDL-C clearance and accelerating atherosclerosis. Methods: Liver-specific epsin knockout (Liver-DKO) atherosclerotic models were generated in ApoE-/- and PCSK9-AAV8-induced atheroprone mice fed on a Western diet. We utilized single-cell RNA sequencing, along with molecular, cellular, and biochemical analyses, to investigate the physiological role of liver epsins in PCSK9-mediated LDLR degradation. Additionally, we explored the therapeutic potential of nanoparticle-encapsulated siRNAs targeting epsins 1 and 2 in ApoE-/- mice with established atherosclerosis. Results: Western diet (WD)-induced atherosclerosis was significantly attenuated in ApoE-/-/Liver-DKO mice compared with ApoE-/- controls, as well as in PCSK9-AAV8-induced Liver-DKO mice compared with PCSK9-AAV8-induced wild-type (WT) mice accompanied by reductions in blood cholesterol and triglyceride levels. Mechanistically, single-cell RNA sequencing of hepatocytes and aortas isolated from atherosclerotic ApoE-/- and ApoE-/-/Liver-DKO mice revealed epsin-deficient Ldlrhi hepatocytes with diminished lipogenic potential. Notably, pathway analysis of hepatocytes showed increased LDL particle clearance and enhanced LDLR-cholesterol interactions under WD treatment in ApoE-/-/Liver-DKO mice compared with ApoE-/- controls, correlating with decreased plasma LDL-C levels. Furthermore, pathway analysis of the aortas showed attenuated inflammation and endothelial activation, coupled with reduced lipid uptake, and enhanced cholesterol efflux under WD treatment in ApoE-/-/Liver-DKO mice compared with ApoE-/- controls. Moreover, the absence of liver epsins led to an upregulation of LDLR protein expression in hepatocytes. We further demonstrated that epsins bind LDLR via the ubiquitin-interacting motif (UIM), enabling PCSK9-mediated LDLR degradation. Depleting epsins abolished this degradation, thereby preventing atheroma progression. Lastly, targeting liver epsins with nanoparticle-encapsulated epsins siRNAs effectively ameliorates dyslipidemia and inhibits atherosclerosis progression. These results are consistent with findings showing an increased epsin1 and epsin2 expression in atherosclerotic cardiovascular disease patients. Conclusions: Liver epsins drive atherogenesis by promoting PCSK9-mediated LDLR degradation, thereby elevating circulating LDL-C levels and heightening lesional inflammation. As such, targeting epsins in the liver represents a promising therapeutic strategy to mitigate atherosclerosis by preserving LDLR and enhancing LDL-C clearance in the liver.

Dataset Information

HELZ2 regulates APOB mRNA stability to modulate fatty liver disease and atherosclerosis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets