The Therapeutic Potential of Targeting Hepatic MCT1 in Non-Alcoholic Steatohepatitis

Abstract

Emerging evidence supports substrate overload to the liver as an initial driver of non-alcoholic steatohepatitis (NASH) progression. Metabolic disease patients have increased plasma lactate levels. Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases. Indeed, monocarboxylate transporter 1 (MCT1) haploinsufficiency in mice causes resistance to diet-induced obesity, steatosis, and hepatic inflammation. However, little is known about the therapeutic potential of hepatic MCT1 and its contribution to NASH fibrogenesis. In this study, we developed novel adeno-associated virus (AAV) lecithin-retinol acyltransferase (Lrat)-Cre vectors that selectively target hepatic stellate cells, as well as two types of hepatic MCT1-targeting fully chemically modified siRNA compounds with distinct cell delivery capabilities: Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs. We demonstrated that stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. Similarly, MCT1 silencing by Chol-siRNA decreased liver collagen 1 level in mice, and decreased LX2 stellate cell collagen expression. Interestingly, however, hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis, without alleviating triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 does not appear to be an attractive therapeutic target for NASH. Furthermore, combining our previously developed chemically modified siRNA compound (DGAT2-1473) with Chol-MCT1-siRNA was more effective than Chol-MCT1-siRNA alone in preventing NASH fibrosis, indicating that a dual targeting approach may be most effective for alleviating NASH.