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Clinical Trial
. 2020 Mar 2;130(3):1453-1460.
doi: 10.1172/JCI134165.

Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease

Gordon I Smith  1 , Mahalakshmi Shankaran  2 , Mihoko Yoshino  1 , George G Schweitzer  1 , Maria Chondronikola  1 , Joseph W Beals  1 , Adewole L Okunade  1 , Bruce W Patterson  1 , Edna Nyangau  2 , Tyler Field  2 , Claude B Sirlin  3 , Saswata Talukdar  4 , Marc K Hellerstein  2 , Samuel Klein  1
Affiliations
Clinical Trial

Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease

Gordon I Smith et al. J Clin Invest. .

Abstract

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.

Keywords: Hepatology; Insulin; Metabolism; Obesity.

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Conflict of interest statement

Conflict of interest: SK receives research funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., and Janssen Pharmaceuticals, and has served as a consultant for Pfizer, Novo Nordisk, and Merck Sharp & Dohme Corp. MKH receives research funding from Gilead Sciences, Pfizer, and Synergenics. ST is an employee and shareholder of Merck & Co.

Figures

Figure 1
Figure 1. Relationships among hepatic DNL and metabolic characteristics.
(A) Relative contribution of DNL to IHTG content, assessed as palmitate produced by DNL, measured in plasma TG–rich lipoprotein TGs (TRL-TGs) in 3 groups of subjects: lean with normal IHTG content (Lean; n = 14); obese with normal IHTG content (Obese; n = 26); and obese with NAFLD (Obese-NAFLD; n = 27). Values indicate the mean ± SEM. One-way ANOVA was performed to compare the relative contribution of DNL to TRL-TG palmitate, with Tukey’s post hoc test used to identify significant mean differences between groups. *Value significantly different from the lean group value, P < 0.05. †Value significantly different from the obese group value, P < 0.01. Relationships between hepatic DNL, assessed as the percentage of contribution of DNL to plasma TRL-TG palmitate and (B) IHTG content; (C) whole-body insulin sensitivity, assessed as the glucose Rd during a HECP; (D) HISI; and integrated 24-hour AUCs for plasma (E) insulin and (F) glucose. Logarithmic regression analysis was used to determine the lines of best fit to the data. White, gray, and black circles represent participants in the lean, obese, and obese-NAFLD groups, respectively.
Figure 2
Figure 2. Moderate weight loss decreases hepatic DNL and IHTG content in subjects with obesity and NAFLD.
Relative contribution of DNL to IHTG content, assessed as palmitate produced by DNL within plasma TRL-TG palmitate (A) and IHTG content (B) before and after a weight loss of approximately 10% in 6 individuals with obesity and NAFLD. Values indicate the mean ± SEM. Circles represent individual values before and after weight loss. Student’s t test for paired samples was used to assess the statistical significance of differences in values before and after weight loss. Asterisks indicate the value significantly different from the before value, P < 0.05.
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