Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Mitochondrial uncoupler MB3 improves liver steatosis and promotes gut microbiota remodeling in a mouse model of non-alcoholic steatohepatitis. (#154)

Martina Beretta 1 , Joseph M Salamoun 2 , Elias N Glaros 1 , Stephanie J Alexopoulos 1 , Nadeem O Kaakoush 3 , Ellen M Olzomer 1 , Divya P Shah 1 , Sing-Young Chen 1 , Sela T Pouha 1 , Brendan Lee 4 , Carolin Lackner 5 , Mark Febbraio 6 , Stefan R Hargett 7 , Webster L Santos 2 , Kyle L Hoehn 1 7
  1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW , Australia
  2. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia , United States
  3. School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  4. Biological Resources Imaging Laboratory, University of New South Wales, Sydney, NSW, Australia
  5. Institute of Pathology, Medical University of Graz, Graz, Austria
  6. Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
  7. Department of Women’s Health, Oxford University, Oxford, UK

Non-alcoholic fatty liver disease (NAFLD) represents an important health challenge. Non-alcoholic steatohepatitis (NASH) is an advanced form of NAFLD and is strongly linked to obesity and related metabolic disorders. NASH is estimated to occur in 20% of individuals affected by NAFLD and leads to an increased mortality risk for both liver- and non-liver-related complications. With a rising prevalence worldwide and limited effective treatment options, there is an urgent need to find new medications. In recent years, there has been increased interest in exploring the potential of mitochondrial uncouplers for the treatment of NASH. Here, we report the discovery of mitochondrial uncoupler MB3 as a maximally orally available compound with a 5.7-hour oral half-life in C57BL/6J mice, and we demonstrate its therapeutic potential in diet-induced mouse models of NASH. In mice fed AMLN diet with and without streptozotocin, chronic treatment with MB3 effectively lowered adiposity and liver triglyceride content. Histological analysis revealed marked improvement in NASH-associated liver pathology, primarily driven by decreased steatosis. In a biopsy-confirmed mouse model of NASH, MB3 reversed liver steatosis while also altering gut microbiota composition. Furthermore, MB3 demonstrates superiority in lowering body weight gain and adiposity over MGL-3196 (Resmetirom), the first and only medication approved by the FDA for the treatment of NASH. Our findings therefore highlight the potential of MB3 as a development candidate for NASH therapy.