Sex-Specific Differences in NAFLD Risk Examined

Unraveling the Mystery of Troglitazone Hepatotoxicity
Unraveling the Mystery of Troglitazone Hepatotoxicity
Differences in hepatic fat oxidation may explain higher prevalence, risk for nonalcoholic fatty liver disease in men.

Lower dietary fatty acid oxidation and prolonged increase in de novo lipogenesis (DNL) may explain the increased prevalence and risk for nonalcoholic fatty liver disease (NAFLD) in men, according to data published in the Journal of Clinical Endocrinology & Metabolism.

More men than women have hepatic steatosis in most populations, the researchers noted, though the potential reasons driving this difference have not been well characterized.

“The reason for sexual dimorphism in prevalence and risk of NAFLD remains unclear but will depend, to some degree on the balance between the availability and removal of [fatty acids] in the liver; the transition from fasted to fed state is likely to fundamentally alter hepatic fatty acid partitioning,” they wrote.

To investigate this further, the researchers sought to evaluate hepatic fatty acid metabolism and partitioning in 11 men and 11 women before and after consumption of a mixed meal using substrates labeled with stable-isotope tracers (2H2O and [U13C]palmitate). They also assessed dietary fatty acid oxidation by the appearance of 13C into plasma 3-hydroxybutyrate (3OHB) and breath CO2 as markers of liver and whole-body fatty acid oxidation, respectively.

Markers of cholesterol and bile acid metabolism as alterations were also evaluated.

Results showed that fasting and postprandial plasma triacylglycerol concentrations were significantly higher in men vs. women, despite similar liver fat content (P<.05).

In women, the appearance of 13C from dietary fatty acid into plasma 3OHB and breath CO2 was greater than in men (P<.05).

The contribution of DNL into VLDL-triacylglycerol was similar, about 10%, in the fasting state, but a divergence was noted in the pattern throughout the study. Specifically, men maintained a higher contribution of DNL to VLDL-triacylglycerol, as compared with women (P=.006 time x sex interaction).

“Our data show that differences in intrahepatic [fatty acid] partitioning and DNL may go some way to explaining this sexual dimorphism,” the researchers wrote. “Our data indicate sex-specific differences in the regulation of oxidation and the hepatic DNL with men failing to suppress DNL as fast as women, thus cellular metabolism is moved away from [fatty acid] oxidation towards esterification.”


  1. Pramfalk C, Pavlides M, Banerjee R, et al. Sex-specific differences in hepatic fat oxidation and synthesis may explain the higher propensity for NAFLD in men. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-2649.