The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR

• DOI: 10.1016/j.molmet.2022.101566
• Publication Date: 2022-08-06T03:50:24Z
• Authors: Janos Steffen; Jennifer Ngo; Sheng-Ping Wang; Kevin Williams; Henning F. Kramer; George Ho; Carlos Rodriguez; Krishna Yekkala; Chidozie Amuzie; Russell Bialecki; Lisa Norquay; Andrea R. Nawrocki; Mark Erion; Alessandro Pocai; Orian S. Shirihai; Marc Liesa
• Keywords: Oma1; 570; Physiology; Chronic Liver Disease and Cirrhosis; Drp1; Inbred C57BL; Small Interfering; Diet, High-Fat; Mitochondrial Dynamics; Oral and gastrointestinal; Mice; 03 medical and health sciences; Weight Loss; 2.1 Biological and endogenous factors; Animals; Aetiology; ISR; Atf4; RNA, Small Interfering; Internal medicine; Metabolic and endocrine; Nutrition; Inflammation; 0303 health sciences; Liver Disease; Prevention; NASH; Biological Sciences; RC31-1245; Fibrosis; Diet; Mitochondria; 3. Good health; Mice, Inbred C57BL; High-Fat; Liver; Biochemistry and cell biology; RNA; Original Article; Biochemistry and Cell Biology; Digestive Diseases

The mitochondrial fission protein Drp1 was proposed to promote NAFLD, as inhibition of hepatocyte early in life prevents liver steatosis induced by high-fat diet mice. However, whether Drp1-knockdown older mice can reverse established NASH is unknown. N-acetylgalactosamine-siRNA conjugates, an FDA approved method deliver siRNA selectively hepatocytes, were used knockdown hepatocyte-Drp1 (NAG-Drp1si). C57BL/6NTac Gubra-Amylin-NASH (D09100310, 40% fat, 22% fructose and 2% cholesterol) treatment with NAG-Drp1si started at week 24 diet. Circulating transaminases, histology, gene expression fibrosis inflammation markers, hydroxyproline synthesis determined severity. Liver NEFA triglycerides quantified GC/MS. Mitochondrial function respirometry. Western blots Oma1, Opa1, p-eIf2α, well transcriptional analyses Atf4-regulated genes ISR engagement. decreased body weight adult healthy Increased hepatic Gdf15 production the major contributor body-weight loss caused treatment, receptor deletion (Gfral KO) prevented decrease food intake mitigated loss. activated Atf4-controlled integrated stress response (ISR) increase expression. ER protease which are triggers that activate ISR. Remarkably, induction not sufficient Oma1 liver. NASH, exacerbating NASH-induced stress. Consequently, led higher activation, exacerbated inflammation, necrosis. mitigates decreasing stress, preventing activation exacerbation. elevation actions might represent adaptive nutrient load when mitochondria misfunctional. Our study argues against blocking hepatocytes combat NASH.