Impaired Hepatic Ketogenesis in Moderately Obese Men With Hypertriglyceridemia

BackgroundSeveral studies suggest that increased nonesterified fatty acid flux and increased de novo lipogenesis may contribute to hypertriglyceridemia, but few studies have examined fatty acid oxidation as a factor.RationaleEndogenous hypertriglyceridemia (increased very low density lipoprotein triglyceride) could result from (a) re-esterification of excess nonesterified fatty acids entering the liver, (b) activation of hepatic lipogenesis, and/or (c) defective oxidation of hepatic fatty acids leading to greater triglyceride synthesis. Therefore, this study used plasma levels of 3-hydroxybutyrate as a marker for fatty acid oxidation. The study was carried out in hypertriglyceridemic and normotriglyceridemic subjects under 3 conditions: (a) in the fasting state, (b) after a fatty meal that should enhance fatty acid oxidation, and (c) after an oxandrolone challenge, which we recently showed increases fatty acid oxidation.ResultsIn the fasting state, 3-hydroxybutyrate concentrations in hypertriglyceridemic patients were only 53% of levels in normotriglyceridemic subjects. After a fatty meal, moderate increases in 3-hydroxybutyrate were observed, but values for patients with hypertriglceridemia remained 62% of the levels in the normotriglyceridemic group. A similar pattern of response was observed with oxandrolone challenge. There were no significant changes in fasting or postprandial levels of nonesterfified fatty acids, glycerol, or triglycerides before and during the oxandrolone challenge.ConclusionPatients with endogenous hypertriglyceridemia seem to have a defect in fatty acid oxidation as indicated by reduced levels of 3-hydroxybutyrate. This defect was observed during fasting, postprandially, and during oxandrolone challenge. We propose that this defect contributes to the development of hypertriglyceridemia.

Carbohydrate-Induced Hypertriglyceridemia: An Insight into the Link between Plasma Insulin and Triglyceride Concentrations*

This study was initiated to test the hypothesis that endogenous hypertriglyceridemia results from a defect in the ability of insulin to inhibit the release of very low-density lipoprotein-triglyceride (TG) from the liver. To accomplish this goal, plasma glucose, insulin, free fatty acid (FFA), and TG concentrations were compared in 12 healthy volunteers, in response to diets containing either 40% or 60% of total calories as carbohydrate (CHO). The protein content of the two diets was similar (15% of calories), and the fat content varied inversely with the amount of CHO (45% or 25%). The diets were consumed in random order, and measurements were made of plasma glucose, insulin, FFA, and TG concentrations at the end of each dietary period, fasting, and at hourly intervals following breakfast and lunch. The results indicated that the 60% CHO diet resulted in higher fasting plasma TG concentrations associated with higher day-long plasma insulin and TG concentrations, and lower FFA concentrations. These results do not support the view that hypertriglyceridemia is secondary to a failure of insulin to inhibit hepatic TG secretion.