Hepatocyte mARC1 promotes fatty liver disease.

Autor:	Lewis LC; Novo Nordisk Research Centre Oxford, Oxford, UK., Chen L; Novo Nordisk Research Centre Oxford, Oxford, UK., Hameed LS; Novo Nordisk Research Centre Oxford, Oxford, UK., Kitchen RR; Novo Nordisk Research Centre Oxford, Oxford, UK., Maroteau C; Novo Nordisk Research Centre Oxford, Oxford, UK., Nagarajan SR; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK., Norlin J; Novo Nordisk A/S, Måløv, Denmark., Daly CE; Novo Nordisk Research Centre Oxford, Oxford, UK., Szczerbinska I; Novo Nordisk Research Centre Oxford, Oxford, UK., Hjuler ST; Novo Nordisk A/S, Måløv, Denmark., Patel R; Novo Nordisk Research Centre Oxford, Oxford, UK., Livingstone EJ; Novo Nordisk Research Centre Oxford, Oxford, UK., Durrant TN; Novo Nordisk Research Centre Oxford, Oxford, UK., Wondimu E; Dicerna Pharmaceuticals Inc., Lexington, MA, USA., BasuRay S; Dicerna Pharmaceuticals Inc., Lexington, MA, USA., Chandran A; Novo Nordisk Research Centre Oxford, Oxford, UK., Lee WH; Dicerna Pharmaceuticals Inc., Lexington, MA, USA., Hu S; Novo Nordisk Research Centre Oxford, Oxford, UK., Gilboa B; Novo Nordisk Research Centre Oxford, Oxford, UK., Grandi ME; Novo Nordisk Research Centre Oxford, Oxford, UK., Toledo EM; Novo Nordisk Research Centre Oxford, Oxford, UK., Erikat AHA; Novo Nordisk Research Centre Oxford, Oxford, UK., Hodson L; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital Trusts, Oxford, UK., Haynes WG; Novo Nordisk Research Centre Oxford, Oxford, UK., Pursell NW; Dicerna Pharmaceuticals Inc., Lexington, MA, USA., Coppieters K; Novo Nordisk A/S, Måløv, Denmark., Fleckner J; Novo Nordisk A/S, Måløv, Denmark., Howson JMM; Novo Nordisk Research Centre Oxford, Oxford, UK., Andersen B; Novo Nordisk A/S, Måløv, Denmark., Ruby MA; Novo Nordisk Research Centre Oxford, Oxford, UK.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2023 Feb 03; Vol. 5 (5), pp. 100693. Date of Electronic Publication: 2023 Feb 03 (Print Publication: 2023).
DOI:	10.1016/j.jhepr.2023.100693
Abstrakt:	Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 ( MTARC1 ) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1 . In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N -acetylgalactosamine (GalNAc)-siRNA to understand the in vivo impacts of MTARC1 . Results: We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant ( p.A165T, rs2642438 G>A ), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and in vivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo . Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. Impact and Implications: We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 for NAFLD. Competing Interests: A provisional patent application directed to the subject matter disclosed in this manuscript has been filed by Novo Nordisk A/S. LCL, LC, LSH, RRK, CM, JN, CED, STH, RP, IS, EJL, TND, AC, SH, BG, MEG, ETM, AHAE, WGH, KC, JF, JMMH, BA, and MAR are Novo Nordisk A/S or Novo Nordisk Ltd employees. EW and NWP are former Dicerna employees. SBR is a former employee of Dicerna Pharmaceuticals Inc. and presently employed by the Novartis Institutes for BioMedical Research (NIBR), Cambridge, MA, USA. WL is a former employee of Dicerna Pharmaceuticals and presently employed with Biogen Inc, Cambridge, MA, USA. LH is a scientific consultant for Novo Nordisk A/S. The remaining authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2023 The Author(s).)
Databáze:	MEDLINE
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