Diabetologie und Stoffwechsel 2016; 11 - P163
DOI: 10.1055/s-0036-1580910

Slc13a5/mINDY inhibition prevents diet-induced non-alcoholic fatty liver disease in mice and rats

S Brachs 1, AF Winkel 2, H Tang 1, AL Birkenfeld 1, 3, H Glombik 2, A Dudda 2, B Brunner 2, K Jahn-Hofmann 2, D Margerie 2, AW Herling 2, H Ruetten 2, D Schmoll 2, J Spranger 1
  • 1Charité – Universitätsmedizin Berlin Center for Cardiovascular Research (CCR), Department of Endocrinology, Diabetes and Nutrition, Berlin, Germany
  • 2Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany
  • 3University Hospital Carl Gustav Carus at the TU Dresden, Department of internal Medicine III, Dresden, Germany

Aims: Non-alcoholic fatty liver disease (NAFLD) is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mINDY). Genetic deletion in mice protected from diet-induced adiposity and insulin resistance. Here, we investigated the effects of inducible and/or liver-specific inactivation of mINDY in two independent rodent models. We hypothesized that hepatic mINDY inhibition can prevent the development of fatty liver and hepatic insulin resistance.

Methods: We identified a chemical mINDY inhibitor (RA47) and studied the effect of a 10-day treatment on the development of NALFD in rats on high-sucrose diet by measuring caloric intake, weight gain and glucose tolerance. The effects of an induced liver-specific siRNA-based mINDY knockdown were studied in mice over an 8-week western diet using metabolic characterization, ipGTT and a hyperinsulinemic-euglycemic clamp.

Results: We demonstrated that mINDY inhibition prevented diet-induced hepatic lipid accumulation of either siRNA-treated mice or rats short-term treated with RA47, respectively. Additionally, siRNA-mediated mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production). No effect on weight gain was observed within the time-frame of the mouse experiment, while the short-term inhibitor experiment in rats revealed reduced food intake and consequently reduced body weight.

Conclusions: Inducible mINDY inhibition prevented diet-induced NAFLD and hepatic mINDY expression contributed to hepatic insulin sensitivity. Hence, mINDY inhibition may represent a therapeutic approach for treatment of fatty liver diseases.