Novo Nordisk Research Centre Oxford, Oxford, UK; Corresponding authors. Address: Novo Nordisk Research Centre Oxford, Novo Nordisk Ltd, Innovation Building, Old Road Campus, Roosevelt Drive, OX3 7FZ, Oxford, UK. Tel.: +44-7979927835.
Lingyan Chen
Novo Nordisk Research Centre Oxford, Oxford, UK
L. Shahul Hameed
Novo Nordisk Research Centre Oxford, Oxford, UK
Robert R. Kitchen
Novo Nordisk Research Centre Oxford, Oxford, UK
Cyrielle Maroteau
Novo Nordisk Research Centre Oxford, Oxford, UK
Shilpa R. Nagarajan
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
Jenny Norlin
Novo Nordisk A/S, Måløv, Denmark
Charlotte E. Daly
Novo Nordisk Research Centre Oxford, Oxford, UK
Iwona Szczerbinska
Novo Nordisk Research Centre Oxford, Oxford, UK
Sara Toftegaard Hjuler
Novo Nordisk A/S, Måløv, Denmark
Rahul Patel
Novo Nordisk Research Centre Oxford, Oxford, UK
Eilidh J. Livingstone
Novo Nordisk Research Centre Oxford, Oxford, UK
Tom N. Durrant
Novo Nordisk Research Centre Oxford, Oxford, UK
Elisabeth Wondimu
Dicerna Pharmaceuticals Inc., Lexington, MA, USA
Soumik BasuRay
Dicerna Pharmaceuticals Inc., Lexington, MA, USA
Anandhakumar Chandran
Novo Nordisk Research Centre Oxford, Oxford, UK
Wan-Hung Lee
Dicerna Pharmaceuticals Inc., Lexington, MA, USA
Sile Hu
Novo Nordisk Research Centre Oxford, Oxford, UK
Barak Gilboa
Novo Nordisk Research Centre Oxford, Oxford, UK
Megan E. Grandi
Novo Nordisk Research Centre Oxford, Oxford, UK
Enrique M. Toledo
Novo Nordisk Research Centre Oxford, Oxford, UK
Abdullah H.A. Erikat
Novo Nordisk Research Centre Oxford, Oxford, UK
Leanne Hodson
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
William G. Haynes
Novo Nordisk Research Centre Oxford, Oxford, UK
Natalie W. Pursell
Dicerna Pharmaceuticals Inc., Lexington, MA, USA
Ken Coppieters
Novo Nordisk A/S, Måløv, Denmark
Jan Fleckner
Novo Nordisk A/S, Måløv, Denmark
Joanna M.M. Howson
Novo Nordisk Research Centre Oxford, Oxford, UK
Birgitte Andersen
Novo Nordisk A/S, Måløv, Denmark
Maxwell A. Ruby
Novo Nordisk Research Centre Oxford, Oxford, UK; Corresponding authors. Address: Novo Nordisk Research Centre Oxford, Novo Nordisk Ltd, Innovation Building, Old Road Campus, Roosevelt Drive, OX3 7FZ, Oxford, UK. Tel.: +44-7979927835.
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.
