Sex-Specific Differences in Hepatic Fat Oxidation and Synthesis May Explain the Higher Propensity for NAFLD in Men

Context and Objective: In most populations a greater proportion of men have hepatic steatosis than women. Sex-specific differences in hepatic dietary fatty acid (FA) metabolism have not been well characterized. We compared fasting and postprandial hepatic FA synthesis (de novo lipogenesis [DNL]) and oxidation in men and women. Participants and Methods: Fasting and postprandial hepatic FA metabolism was studied in 22 healthy men (n = 11) and women with similar age, body mass index, and liver fat content using metabolic substrates labeled with stable-isotope tracers (2H(2)O and [(UC)-C-13] palmitate). Dietary FA oxidation was assessed by appearance of C-13 into plasma 3-hydroxybutyrate and breath CO2 as markers of liver and whole-body FA oxidation, respectively. Results: Despite similar liver fat content, fasting and postprandial plasma triacylglycerol (TG) concentrations were significantly (P < .05) higher in men compared with women. The appearance of C-13 from dietary FA into plasma 3-hydroxybutyrate and breath CO2 was greater (P < .05) in women compared with men. Although the contribution of DNL into very low-density lipoprotein (VLDL)-TG was similar (similar to 10%) in the fasting state, there was a divergence in pattern over the course of the study, with men maintaining a higher contribution of DNL to VLDL-TG than women (P = .006 time x sex interaction). Conclusions: The combination of lower dietary FA oxidation and a prolonged increase in DNL observed in men may represent partitioning of FA into esterification and storage pathways within the liver, leading to greater VLDL-TG production, and predispose to the sex difference in hepatic steatosis.