Adipose MTP deficiency protects against hepatic steatosis by upregulating PPAR activity

Title : Adipose MTP deficiency protects against hepatic steatosis by upregulating PPAR activity

Abstract:

MASH is a growing health concern. Better understanding of factors that prevent hepatic lipid accumulation may help design new strategies to prevent or treat MASH. We have previously shown that adipocyte MTP regulates intracellular lipolysis by inhibiting ATGL activity. Here, we show that adipose-specific MTP knockout mice (A-Mttp^−/−) fed an obesogenic diet exhibit moderately high plasma triglyceride levels and less hepatic steatosis compared to their wild-type counterparts. A-Mttp^−/− mice showed increased hepatic TG secretion compared to the wild type mice. Lipidomic analysis revealed significantly higher amounts of oleate, palmitate, linoleate, and stearate in the livers of A-Mttp^−/− mice compared to Mttp^f/f mice. A-Mttp^−/− mice livers also showed significantly increased expression of genes in fatty acid (FA) uptake and utilization compared to Mttp^f/f mice. Wildtype hepatocytes incubated with conditioned media (CM) from Mttp^−/− adipocytes oxidized more FAs. Transcriptome analysis revealed hepatocytes treated with conditioned media (CM) from Mttp^−/− adipocyte have significantly increased expression of genes involved in FA metabolism, oxidation and PPAR signaling compared to hepatocytes treated with Mttp^f/f adipocyte conditioned media. Further mechanistic experiments showed that increased FA oxidation in A-Mttp^−/− liver is mediated by PPARα activation and that adipose-derived FAs play a crucial role in activating liver PPARα. We conclude that increased availability of substrate for TG production might contribute to increased apoB secretion by the liver of A-Mttp^−/− mice. Moreover, a positive adipose liver crosstalk mediated by the release of natural ligands of PPARα protect A-Mttp^−/− mice from hepatic steatosis. Our study highlights the significance of the regulated movement of FFA from adipose tissue to the liver in maintaining a healthy liver. It is likely that adipocyte FA release can be modulated to reduce hepatic steatosis.

Biography:

Dr. Sujith Rajan is Assistant Professor at NYU Long Island School of Medicine, specializing in adipocyte biology and lipid metabolism. He earned his Ph.D. from CSIR-Central Drug Research Institute, India, and has received numerous accolades, including the American Heart Association Postdoctoral Fellowship and the Charles Trey, MD Memorial Liver Scholar Award. Dr. Rajan's pioneering work on microsomal triglyceride transfer protein (MTP) in adipocytes has led to significant publications and a patent. His research aims to understand the role of adipose tissue in metabolic diseases, with a long-term goal to find better therapeutic intervention for obesity and related metabolic diseases.