Investigating a Potential Path to Medication for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in the Czech Lab
People with MASH are at increased risk of developing type 2 diabetes. No approved therapy is yet available.
A significant percentage of people living with type 2 diabetes also have too much fat accumulated in their liver that can develop into metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH) which was formerly known as nonalcoholic steatohepatitis (NASH). It’s characterized by severe liver inflammation and fibrosis that can lead to cirrhosis and may require a liver transplantation. Currently, there are no FDA-approved therapeutics available to specifically address it.
To better understand how a medication might be developed, the Czech lab studied fat production in the liver from carbohydrates by disrupting an enzyme that helps to convert blood glucose into fat in obese mice. Results of their research is published in the Journal of Biological Chemistry (August 2022).
“To our surprise, when we blocked this enzyme, we found higher fat synthesis not less,” said Michael Czech, PhD, the Isadore and Fannie Foxman Chair in Medical Research and professor of molecular medicine at UMass Chan Medical School. “We tracked this down to a way that the liver gets around this enzyme to produce fat, and now we see this new pathway as an opportunity to explore how a medication might be developed.”
Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice
Batuhan Yenilmez 1, Mark Kelly 1, Guofang Zhang 2, Nicole Wetoska 1, Olga R Ilkayeva 2, Kyounghee Min 1, Leslie Rowland 1, Chloe DiMarzio 1, Wentao He 2, Naideline Raymond 1, Lawrence Lifshitz 1, Meixia Pan 3, Xianlin Han 3, Jun Xie 4, Randall H Friedline 1, Jason K Kim 1, Guangping Gao 4, Mark A Herman 2, Christopher B Newgard 5, Michael P Czech 6 PMID: 35988648 DOI: 10.1016/j.jbc.2022.102401
Another study led by Batuhan Yenilmez, PhD, Assistant Professor in the Czech lab, targeted genes that promote fatty liver and inflammation in obesity and diabetes with short-interfering RNA (siRNA)-induced RNAi as a potential therapy.
“We’re targeting gene products known to enhance fatty liver and MASH in animal models,” said Dr. Yenilmez. “Our ultimate goal is to advance this technology and treatment to human clinical trials."
RNAi-based therapeutics is revolutionizing the treatment of liver diseases. Recent chemical advances supporting long-term gene silencing are using an injection, similar to an insulin shot.
In the study published in the scientific journal Molecular Therapy, Yenilmez and his colleagues performed preclinical studies using “humanized mice” from the UMass Diabetes Center of Excellence laboratory of Michael Brehm, PhD. The humanized model was used to show that their compound can successfully target human mRNA in vivo. The collaborative research included the lab of Anastasia Khvorova, PhD from the UMass Chan RNA Therapeutics Institute and Program in Molecular Medicine.
An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis
Batuhan Yenilmez 1, Nicole Wetoska 1, Mark Kelly 1, Dimas Echeverria 2, Kyounghee Min 1, Lawrence Lifshitz 1, Julia F Alterman 2, Matthew R Hassler 2, Samuel Hildebrand 2, Chloe DiMarzio 1, Nicholas McHugh 2, Lorenc Vangjeli 2, Jacquelyn Sousa 2, Meixia Pan 3, Xianlin Han 3, Michael A Brehm 1, Anastasia Khvorova 4, Michael P Czech 5PMID: 34774753 PMCID: PMC8899521 DOI: 10.1016/j.ymthe.2021.11.007
Upon injection into genetically obese NASH mice, the therapy resulted in up to three months of success deleting the intended gene(s), plus significant improvement of the fatty liver phenotype. The reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. So, while it could be a practical, long-lasting silencing agent for a potential liver steatosis therapy, combinatorial targeting of a second pathway may be necessary for success against NASH.
“Advances in siRNA design and chemistry have already overcome many previous limitations,” said Dr. Czech. “Our research team has already begun additional studies to get us closer to the end goal.”
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