Sepideh Mikaeeli, PhD

Irwin M. Arias, MD Postdoctoral Research Fellowship Award
$25,000 over one year

Cedar- Sinai Medical Center

Muscle-Specific Control of Lipid Metabolism by Thioesterase Superfamily Member 2 (Them2) in the Pathogenesis of MASLD

Mentor: David Cohen, MD, PhD

Despite the central role of skeletal muscle in energy homeostasis and interorgan communication, and the multisystem origins of metabolic dysfunction-associated steatotic liver disease (MASLD), the role and importance of muscle in the pathogenesis of MASLD remain unanswered. The objective of this work is to elucidate the role of two lipid-related proteins, thioesterase superfamily member 2 (Them2) and phosphatidylcholine transfer protein (PC-TP), in skeletal muscle insulin signaling and its communication with the liver under conditions of overnutrition. Our main question is how these proteins regulate insulin sensitivity and extracellular vesicle (EV) signaling in muscle during lipid dysregulation and how these subsequent changes affect liver function. The rationale for this work is based on the established role of muscle in insulin and lipid signaling, and the understanding that alterations in these pathways contribute to the development of MASLD. Indeed, prior evidence highlights the involvement of the Them2-PC-TP-p38 MAPK axis in muscle insulin signaling pathways. We hypothesize that Them2 promotes insulin resistance and metabolic dysfunction by directing saturated fatty acids into stress-activated pathways, such as MKP-1-mediated regulation of p38 MAPK, and modifying EV composition, thereby driving hepatic steatosis under overnutrition conditions. Our approach involves two specific aims: Aim 1 utilizes skeletal muscle-specific knockout mouse models of Them2 and PC-TP, as well as MKP-1, in combination with AAV8-mediated expression of wild-type and mutant Them2 and PC-TP proteins, along with in vitro studies, to dissect the signaling pathways regulating muscle metabolism and insulin sensitivity. Aim 2 investigates how Them2 and PC-TP influence the composition and function of skeletal muscle-derived EVs, assessing their impact on liver metabolism and MASLD progression under conditions of overnutrition. We expect that Them2 KO will improve insulin sensitivity, reduce ER stress, and enhance fatty acid oxidation in skeletal muscle, while EVs from Them2-deficient muscle will carry protective cargo that mitigates liver steatosis and insulin resistance. Re-expression of Them2 or PC- TP is anticipated to reverse these benefits. This work will define a novel muscle-to-liver communication axis involving Them2 and PC- TP, revealing potential therapeutic targets for MASLD