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

Min, K.; Yenilmez, B.; Kelly, M.; Echeverria, D.; Elleby, M.; Lifshitz, L. M.; Raymond, N.; Tsagkaraki, E.; Harney, S. M.; DiMarzio, C.; McHugh, N.; Bramato, B.; Morrison, B.; Rothstein, J. D.; Khvorova, A.; Czech, M. P.

doi:10.1101/2023.05.03.539244

bioRxiv · 10.1101/2023.05.03.539244

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

Min, K.·Yenilmez, B.·Kelly, M.·Echeverria, D.·Elleby, M.·Lifshitz, L. M.·Raymond, N.·Tsagkaraki, E.·Harney, S. M.·DiMarzio, C.·McHugh, N.·Bramato, B.·Morrison, B.·Rothstein, J. D.·Khvorova, A.·Czech, M. P.

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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.

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Min, K., Yenilmez, B., Kelly, M., Echeverria, D., Elleby, M., Lifshitz, L. M., Raymond, N., Tsagkaraki, E., Harney, S. M., DiMarzio, C., McHugh, N., Bramato, B., Morrison, B., Rothstein, J. D., Khvorova, A., Czech, M. P.. 2023-05-03. Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis. https://doi.org/10.1101/2023.05.03.539244

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