Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis

• Published in: eLife 2024-04, Vol.12
• Main Authors: Min, Kyounghee, Yenilmez, Batuhan, Kelly, Mark, Echeverria, Dimas, Elleby, Michael, Lifshitz, Lawrence M, Raymond, Naideline, Tsagkaraki, Emmanouela, Harney, Shauna M, DiMarzio, Chloe, Wang, Hui, McHugh, Nicholas, Bramato, Brianna, Morrison, Brett, Rothstein, Jeffery D, Khvorova, Anastasia, Czech, Michael P
• Format: Article
• Language: English
• Subjects: AAV; Acyltransferase; Animals; Cell Biology; Cholesterol; Collagen; Collagen - metabolism; Collagen Type I - metabolism; D-Galactosamine; Diabetes; Disease Models, Animal; Disease resistance; Fatty liver; Fibrosis; Genetic vectors; Globulins; Growth factors; Haploinsufficiency; Health aspects; Hepatic Stellate Cells; Hepatocytes; High fat diet; Homeostasis; Humans; Inflammation; Insulin resistance; Lactic acid; Lecithin; Liver; Liver - metabolism; Liver Cirrhosis - pathology; Liver diseases; liver fibrosis; Metabolic disorders; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Obese; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; NAFLD; NASH; Non-alcoholic Fatty Liver Disease - genetics; Nutrient deficiency; Obesity; Phosphatidylcholine-retinol O-acyltransferase; Physiological aspects; Proteins; Retinoids; RNA, Small Interfering - metabolism; RNAi therapeutics; siRNA; Steatosis; Stellate cells; Therapeutic targets; Thyroxine; Triglycerides; Type 2 diabetes; Vitamin A
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.89136

Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1 mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri- -acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on 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 appears not to be an attractive therapeutic target for NASH.