Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 104, Issue 12, Pages 6171-6181Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2019-00875
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [DK40484, DK45343, DK50456]
- National Center for Research Resources, National Institutes of Health [1 UL1 RR024150-01, UL1 TR000135]
- National Center for Advancing Translational Sciences, National Institutes of Health [1 UL1 RR024150-01, UL1 TR000135]
- National Institutes of Health Training Grant [T32-DK07352]
- American Diabetes Association Fellowship Grant [7-112-MN36]
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Objective: Nonalcoholic fatty liver disease can lead to hepatic inflammation/damage. Understanding the physiological mechanisms that contribute to excess hepatic lipid accumulation may help identify effective treatments. Design: We recruited 25 nondiabetic patients with severe obesity scheduled for bariatric surgery. To evaluate liver export of triglyceride fatty acids, we measured very-low-density lipoprotein (VLDL)-triglyceride secretion rates the day prior to surgery using an infusion of autologous [1-C-14]triolein-labeled VLDL particles. Ketone body response to fasting and intrahepatic longchain acylcarnitine concentrations were used as indices of hepatic fatty acid oxidation. We measured intraoperative hepatic uptake rates of plasma free fatty acids using a continuous infusion of [U-C-13] palmitate, combined with a bolus dose of [9,10-H-3]palmitate and carefully timed liver biopsies. Total intrahepatic lipids were measured in liver biopsy samples to determine fatty liver status. The hepatic concentrations and enrichment from [U-C-13]palmitate in diacylglycerols, sphingolipids, and acyl-carnitines were measured using liquid chromatography/tandem mass spectrometry. Results: Among study participants with fatty liver disease, intrahepatic lipid was negatively correlated with VLDL-triglyceride secretion rates (r = 20.92, P = 0.01) but unrelated to hepatic free fatty acid uptake or indices of hepatic fatty acid oxidation. VLDL-triglyceride secretion rates were positively correlated with hepatic concentrations of saturated diacylglycerol (r=0.46, P=0.02) and sphingosine-1-phosphate (r = 0.44, P = 0.03). Conclusion: We conclude that in nondiabetic humans with severe obesity, excess intrahepatic lipid is associated with limited export of triglyceride in VLDL particles rather than increased uptake of systemic free fatty acids.
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