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

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 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-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.

• Authors: Kyounghee Min, Batuhan Yenilmez, Mark Kelly, Dimas Echeverria, Michael Elleby, Lawrence M Lifshitz, Naideline Raymond, Emmanouela Tsagkaraki, Shauna M Harney, Chloe DiMarzio, Hui Wang, Nicholas McHugh, Brianna Bramato, Brett Morrison, Jeffery D Rothstein, Anastasia Khvorova, Michael P Czech
• Journal: eLife (Elife) Vol. 12 (Apr 02 2024) ISSN: 2050-084X [Electronic] England
• PMID: 38564479 (Publication Type: Journal Article)
• Copyright: © 2023, Min et al.

Chemical References

• Collagen
• Collagen Type I
• Monocarboxylic Acid Transporters
• RNA, Small Interfering
• monocarboxylate transport protein 1

Topics

• Animals
• Humans
• Mice
• Collagen (metabolism)
• Collagen Type I (metabolism)
• Disease Models, Animal
• Hepatic Stellate Cells
• Liver (metabolism)
• Liver Cirrhosis (pathology)
• Mice, Inbred C57BL
• Mice, Obese
• Monocarboxylic Acid Transporters (genetics, metabolism)
• Non-alcoholic Fatty Liver Disease (genetics)
• RNA, Small Interfering (metabolism)