(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis

• DOI: 10.1161/circresaha.117.312422
• Publication Date: 2018-01-04T10:15:44Z
• Authors: Liwei Ren; Yuan Sun; Hong Lu; Dien Ye; Lijuan Han; Na Wang; Alan Daugherty; Furong Li; Miaomiao Wang; Fengting Su; Wenjun Tao; Jie Sun; Noam Zelcer; Adam E. Mullick; A.H. Jan Danser; Yizhou Jiang; Yongcheng He; Xiongzhong Ruan; Xifeng Lu
• Keywords: Male; 0301 basic medicine; hypertriglyceridemia; Pyruvate Dehydrogenase Complex; Receptors, Cell Surface; liver; Diet, High-Fat; Mice; 03 medical and health sciences; vacuolar H+-ATPase; SDG 3 - Good Health and Well-being; Animals; Humans; Gene Silencing; Obesity; Prorenin Receptor; renin–angiotensin system; Cells, Cultured; 2. Zero hunger; hypercholesterolemia; dyslipidemia; Hep G2 Cells; Lipid Metabolism; EMC COEUR-09-39-02; 3. Good health; Fatty Liver; Mice, Inbred C57BL; Adaptor Proteins, Vesicular Transport; Hepatocytes; Acetyl-CoA Carboxylase

Rationale: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates metabolism in vitro via LDLR (LDL receptor) and SORT1 (sortilin-1), independently renin–angiotensin system. Objectives: To investigate physiological role (P)RR lipid vivo. Methods Results: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic expression C57BL/6 mice studied consequences this has on metabolism. In line with our earlier report, silencing increased LDL-C cholesterol). Unexpectedly, also resulted markedly reduced triglycerides a SORT1-independent manner fed normal- or high-fat diet. LDLR-deficient mice, inhibition both cholesterol triglycerides, diet-independent manner. Mechanistically, found decreased protein abundance ACC (acetyl-CoA carboxylase) PDH (pyruvate dehydrogenase). This alteration reprograms metabolism, leading synthesis fatty acid oxidation. As result, attenuated diet-induced obesity hepatosteatosis. Conclusions: Collectively, study suggests plays key energy homeostasis regulation lipids by integrating glucose