Adipose microsomal triglyceride transfer protein deficiency protects against hepatic steatosis by upregulating PPARα activity

Background & Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health issue. Identifying factors that prevent hepatic lipid accumulation could inform new MASLD prevention or treatment strategies. We previously demonstrated that adipocyte microsomal triglyceride transfer protein (MTP) regulates intracellular lipolysis by inhibiting adipose triglyceride lipase activity. The aim of this study was to investigate the impact of adipose MTP deficiency on MASLD. Methods: We used previously described adipose-specific MTP knockout (A-Mttp^−/−) mice. Fat mobilization from adipose to liver was assessed using: (1) lipidomic profiling of plasma, epididymal fat, and liver, and (2) treatment of wild-type hepatocytes with conditioned media from MTP-deficient adipocytes. Fatty acid (FA) oxidation was evaluated using ¹⁴C-oleate. Transcriptome analysis, quantitative reverse-transcription PCR and western blotting were performed to determine gene expression. PPARα activity was assessed using a reporter assay. Results: A-Mttp^−/− mice on an obesogenic diet exhibited moderately elevated plasma triglyceride levels and less hepatic steatosis compared to wild-type mice (n = 3-4 per group; two-way repeated measures ANOVA p = 0.0076). Elevated plasma triglyceride levels in A-Mttp^−/− mice were attributable to increased hepatic triglyceride synthesis and production of triglyceride-rich lipoproteins. Additionally, hepatocytes from these mice showed elevated FA oxidation. Mechanistic studies indicated a positive adipose-liver crosstalk involving upregulation of hepatic PPARα activity by adipose-derived FAs, likely protecting A-Mttp^−/− mice from hepatic steatosis. Conclusion: These findings highlight the importance of regulated FA flux from adipose tissue to the liver and the liver's adaptive capacity to utilize adipose-derived FAs in maintaining hepatic health. Modulation of adipocyte FA release may represent a therapeutic strategy to reduce hepatic steatosis. Impact and implications: This study provides significant insights into the role of adipose-specific microsomal triglyceride transfer protein in regulating hepatic lipid metabolism and its potential implications for treating metabolic dysfunction-associated steatotic liver disease. By demonstrating that microsomal triglyceride transfer protein deficiency in adipose tissue leads to increased fatty acid oxidation and reduced hepatic steatosis through enhanced PPARα activation, the research underscores the importance of adipose-liver crosstalk in maintaining liver health. These findings suggest that targeting adipocyte fatty acid release could be a promising therapeutic strategy to mitigate hepatic lipid accumulation and combat metabolic dysfunction-associated steatotic liver disease, offering a novel approach to addressing this growing health issue.