Targeting Liver Cell-Specific Lactate Transport in the Czech Lab to Potentially Treat Chronic Liver Disease
Metabolic-dysfunction associated steatotic liver disease (MASLD) is a growing global health concern, affecting more than a quarter of the world's population. This chronic liver condition can progress from simple fat accumulation to the more severe metabolic-dysfunction associated steatohepatitis (MASH), which can lead to permanent liver damage, cirrhosis, and liver cancer.
Research conducted in the Czech laboratory uncovered an important role for the lactate transporter MCT1 in the development of MASH, with a surprising twist. “Lactate is a byproduct of metabolism that can build up in the body, especially in conditions like obesity and diabetes,” said Batuhan Yenilmez, PhD, Assistant Professor in the Czech lab at UMass Chan Medical School. “The lactate transporter MCT1 are proteins that help to move lactate in and out of our cells. Altering this transport in a cell-type specific manner has completely different outcomes in MASH.”
Their findings, published in the journal eLife, suggest that targeting MCT1 in specific liver cell types could lead to a promising therapeutic approach. They found that depletion of MCT1 specifically in hepatic stellate cells, which are the major contributors to liver fibrosis, significantly reduced collagen production and fibrosis in mouse models of NASH. The study was led by graduate student Kyounghee Min, who is now a postdoctoral researcher in Dallas at UT Southwestern Medical Center.
"Surprisingly, when we knocked out MCT1 in hepatocytes, the main liver cell type, it actually increased fibrosis, without affecting fat accumulation," explained Michael Czech, PhD, The Isadore & Fannie Foxman Chair of Medical Research, Program in Molecular Medicine.
This suggests that MCT1 in hepatic stellate cells, rather than hepatocytes, plays a crucial role in promoting the fibrotic progression of MASH. Silencing MCT1 in cultured human stellate cells also inhibited the production of collagen, the hallmark of fibrosis.
"Our findings underscore the importance of targeting the right cell type to effectively treat MASH," added Dr. Yenilmez. "Modulating MCT1 function specifically in hepatic stellate cells may be a promising strategy to prevent or reverse the fibrotic damage in fatty liver disease."
The Czech lab has also developed new tools, such as cell-type specific viral vectors, that can be used to further investigate the role of MCT1 in different liver cell populations during MASLD/MASH progression. This study provides important insights into the complex pathogenesis of MASH and creates new avenues for the development of targeted therapies against this debilitating liver condition.
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 LM, Raymond N, Tsagkaraki E, Harney SM, DiMarzio C, Wang H, McHugh N, Bramato B, Morrison B, Rothstein JD, Khvorova A, Czech MP. Elife. 2024 Apr 2;12:RP89136. doi: 10.7554/eLife.89136. PMID: 38564479
Related Articles
Type 2 Diabetes Research in the Czech Lab Investigating Beige Fat to Potentially Increase Metabolism
Type 2 Diabetes Researcher Spotlight: Adilson Guilherme, PhD