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- Title
Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis.
- Authors
Kyounghee Min; Yenilmez, Batuhan; Kelly, Mark; Echeverria, Dimas; Elleby, Michael; Lifshitz, Lawrence M.; Raymond, Naideline; Tsagkaraki, Emmanouela; Harney, Shauna M.; DiMarzio, Chloe; Hui Wang; McHugh, Nicholas; Bramato, Brianna; Morrison, Brett; Rothstein, Jeffery D.; Khvorova, Anastasia; Czech, Michael P.
- Abstract
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 MCT1fl/fl mice on a cholinedeficient, 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-N-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.
- Subjects
LIVER cells; NON-alcoholic fatty liver disease; HEPATIC fibrosis; COLLAGEN; MONOCARBOXYLATE transporters; LACTATES
- Publication
eLife, 2024, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.89136