Lipodystrophic gene Agpat2 deficiency aggravates hyperlipidemia and atherosclerosis in Ldlr-/- mice

Kenan Peng; Xin Chen; Kexin Pei; Xiaowei Wang; Xindi Ma; Chenxi Liang; Qianqian Dong; Ziwei Liu; Mei Han; George Liu; Hongyuan Yang; Mingqi Zheng; Gang Liu; Mingming Gao

doi:10.1016/j.bbadis.2023.166850

Lipodystrophic gene Agpat2 deficiency aggravates hyperlipidemia and atherosclerosis in Ldlr^-/- mice

Biochim Biophys Acta Mol Basis Dis. 2024 Jan;1870(1):166850. doi: 10.1016/j.bbadis.2023.166850. Epub 2023 Aug 15.

Authors

Kenan Peng¹, Xin Chen², Kexin Pei³, Xiaowei Wang⁴, Xindi Ma⁴, Chenxi Liang⁴, Qianqian Dong⁵, Ziwei Liu⁴, Mei Han⁶, George Liu⁷, Hongyuan Yang⁸, Mingqi Zheng⁹, Gang Liu¹⁰, Mingming Gao¹¹

Affiliations

¹ Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Laboratory Department of Hebei General Hospital, Shijiazhuang, Hebei 050051, China.
² Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Department of General Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, China.
³ Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, China.
⁴ Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
⁵ Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
⁶ Department of Biochemistry and Molecular Biology, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
⁷ Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, School of Basic Medical Sciences, Peking University, Beijing, China.
⁸ School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW 2052, Australia.
⁹ Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, China. Electronic address: mzheng2020@163.com.
¹⁰ Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, China. Electronic address: cardio2004@163.com.
¹¹ Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei 050017, China. Electronic address: g.m0515@163.com.

PMID: 37591406
DOI: 10.1016/j.bbadis.2023.166850

Abstract

Aims: Dysfunction of adipose tissue increases the risk of cardiovascular disease. It was well established that obesity aggravates atherosclerosis, but the effect of adipose tissue loss on atherosclerosis has been less studied. AGPAT2 is the first causative gene of congenital generalized lipodystrophy (CGL), but the role of AGPAT2 on atherosclerosis has not been reported. Hypertriglyceridemia is one of the clinical manifestations of CGL patients, but it is usually absent in CGL mouse model on a normal diet. This study will investigate the effect of Agpat2 on hyperlipidemia and atherosclerosis.

Methods and results: In this study, Agpat2 knockout (Agpat2^-/-) mice were generated using CRISPR/Cas system, which showed severe loss of adipose tissue and fatty liver, consistent with previous reports. Agpat2^-/- mice were then crossed with hypercholesterolemic and atherosclerotic prone LDL receptor knockout (Ldlr^-/-) mice to obtain double knockout mouse model (Agpat2^-/-Ldlr^-/-). Plasma lipid profile, insulin resistance, fatty liver, and atherosclerotic lesions were observed after 12 weeks of the atherogenic high-fat diet (HFD) feeding. We found that compared with Ldlr^-/- mice, Agpat2^-/-Ldlr^-/- mice showed significantly higher plasma total cholesterol and triglycerides after HFD feeding. Agpat2^-/-Ldlr^-/- mice also developed hyperglycemia and hyperinsulinemia, with increased pancreatic islet area. The liver weight of Agpat2^-/-Ldlr^-/- mice was about 4 times higher than that of Ldlr^-/- mice. The liver lipid deposition was severe and Sirius red staining showed liver fibrosis. In addition, in Agpat2^-/-Ldlr^-/- mice, the area of atherosclerotic lesions in aortic arch and aortic root was significantly increased.

Conclusions: Our results show that Agpat2 deficiency led to more severe hyperlipidemia, liver fibrosis and aggravation of atherosclerosis in Ldlr^-/- mice. This study provided additional insights into the role of adipose tissue in hyperlipidemia and atherosclerosis.

Keywords: Agpat2; Atherosclerosis; Hyperlipidemia; Lipodystrophy; Liver fibrosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis* / genetics
Atherosclerosis* / pathology
Fatty Liver* / etiology
Humans
Hyperlipidemias* / complications
Hyperlipidemias* / genetics
Lipodystrophy* / complications
Liver Cirrhosis / complications
Mice
Mice, Knockout
Receptors, LDL / genetics
Triglycerides

Substances

2-acylglycerophosphate acyltransferase
Receptors, LDL
Triglycerides
Ldlr protein, mouse