BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature
of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic
de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The
physiological factors that stimulate hepatic DNL and the effect of weight loss on
hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and
glucose concentrations, and both liver and whole-body insulin sensitivity were determined
in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or
obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method
corrected for the potential confounding contribution of adipose tissue DNL. Liver
and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic
clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD
group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe
contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese,
and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic
and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose
and insulin concentrations. Weight loss decreased IHTG content, in conjunction with
a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese
data suggest hepatic DNL is an important regulator of IHTG content and that increases
in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD.
Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL
REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH
grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center),
DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational
Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation,
the College of Natural Resources of UCB, and the Pershing Square Foundation.