Abstract
Introduction: We have shown that microsomal triglyceride transfer protein (MTP) in adipocytes regulates lipolysis by inhibiting adipose triglyceride lipase (ATGL). Adipose MTP knockout mice (A- Mttp -/- ) exhibit smaller adipocytes, more thermogenesis, and less weight gain on an obesogenic diet. Aim: To investigate the MTP-ATGL interaction in adipocytes and its impact on hepatic lipid metabolism. Methods: We studied MTP-ATGL interactions using in silico modeling, ELISA, and co-IP. Lipoprotein profiles were analyzed using FPLC. Adipose-liver cross-talk was assessed through co-culture experiments, adipokine profiling and lipidomics. Hepatic triglyceride (TG) production and fatty acid (FA) oxidation were assessed using poloxamer-407 and 14 C-palmitate. Statistical analyses were done using GraphPad Prism (P <.05 significant). Results: Our study suggests MTP-ATGL interactions are hydrophobic involving C-terminal of ATGL and N-terminal β-barrel of MTP. These interactions vary in different metabolic states like fasting and adipocyte differentiation. A- Mttp -/- mice had higher plasma TG content in VLDL and LDL fractions. Despite increased movement of FAs from adipose to the liver as indicated by lipidomics of eWAT, plasma and liver, A- Mttp -/- mice liver showed less steatosis. Adipokine profiling showed significantly higher amounts of adiponectin in the plasma of A- Mttp -/- mice. Reduced ceramide levels and significantly increased AMPK phosphorylation suggest higher adiponectin activity in A- Mttp -/- livers. A- Mttp -/- livers showed higher expression of FA uptake and utilization related genes, but no change in lipid synthesis. Hepatocytes treated with Mttp -/- adipocytes conditioned media (CM) showed higher FA oxidation than those treated with Mttp f/f adipocytes CM. Mttp -/- adipocytes CM showed significantly higher PPARα reporter activity than Mttp f/f adipocytes CM. Conclusion: Our study reveals dynamic hydrophobic interactions between MTP and ATGL that vary with metabolic states. Enhanced movement of PPARα ligands (FAs) and adiponectin from A- Mttp -/- adipocytes boosts VLDL production and FA oxidation, to protect livers from hepatic steatosis. This highlights a novel role of adipose MTP in the regulation of hepatic lipid homeostasis.
Published Version
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