Background-Hepatic lipoprotein production has been shown previously to be regulated by free fatty acid (FFA) flux to the liver, whereas intestinal lipoprotein production is stimulated mainly by ingested fat absorbed from the intestinal lumen. Emerging evidence indicates that intestinal lipoprotein production is increased in insulin resistance and type 2 diabetes mellitus, conditions that are associated with increased levels of circulating FFAs. Here we investigated whether short-term elevation of plasma FFAs stimulates intestinal apolipoprotein (apo) B-48 -and hepatic apoB-100 -containing triglyceride-rich lipoprotein (TRL) production in humans in the fed state. Methods and Results-TRL apoB-48 and apoB-100 metabolism were examined in 12 healthy men during a constant fed state. The studies were as follows, respectively: (1) Intralipid/heparin was infused intravenously immediately before and during the kinetics study to induce an Ϸ3-fold difference in plasma FFA compared with the saline study; (2) saline was infused intravenously as a control. ApoB-48 -and apoB-100 -containing TRL production and clearance were determined with a 12-hour primed constant infusion of [D3]L-leucine and multicompartmental kinetic modeling. TRL apoB-48 production rate was 69% higher in the Intralipid/heparin study than in the saline control (5.95Ϯ1.13 versus 3.53Ϯ0.58 mg/kg per day; Pϭ0.027), and there was no significant difference in TRL apoB-48 clearance. TRL apoB-100 concentrations were also increased (PϽ0.001) and TRL apoB-100 production rate was 35% higher in the Intralipid/ heparin study compared with saline (28Ϯ4 versus 21Ϯ3 mg/kg per day; Pϭ0.020). Conclusions-This is the first study to demonstrate that intestinal TRL apoB-48 production is increased after short-term elevation of plasma FFAs in humans in the fed state, similar to the well-described stimulation of hepatic TRL apoB100 -containing particles by FFAs.

OBJECTIVEIntestinal lipoprotein production has recently been shown to be increased in insulin resistance, but it is not known whether it is regulated by insulin in humans. Here, we investigated the effect of acute hyperinsulinemia on intestinal (and hepatic) lipoprotein production in six healthy men in the presence and absence of concomitant suppression of plasma free fatty acids (FFAs).RESEARCH DESIGN AND METHODSEach subject underwent the following three lipoprotein turnover studies, in random order, 4–6 weeks apart: 1) insulin and glucose infusion (euglycemic-hyperinsulinemic clamp) to induce hyperinsulinemia, 2) insulin and glucose infusion plus Intralipid and heparin infusion to prevent the insulin-induced suppression of plasma FFAs, and 3) saline control.RESULTSVLDL1 and VLDL2-apoB48 and -apoB100 production rates were suppressed by 47–62% by insulin, with no change in clearance. When the decline in FFAs was prevented by concomitant infusion of Intralipid and heparin, the production rates of VLDL1 and VLDL2-apoB48 and -apoB100 were intermediate between insulin and glucose infusion and saline control.CONCLUSIONSThis is the first demonstration in humans that intestinal apoB48-containing lipoprotein production is acutely suppressed by insulin, which may involve insulin's direct effects and insulin-mediated suppression of circulating FFAs.

OBJECTIVEThe metabolism of hepatic- and intestinally derived lipoproteins is regulated in a complex fashion by nutrients, hormones, and neurologic and other factors. Recent studies in animal models suggest an important role for glucagon acting via the glucagon receptor in regulating hepatic triglyceride (TG) secretion. Here we examined the direct effects of glucagon on regulation of hepatic and intestinal lipoprotein metabolism in humans.RESEARCH DESIGN AND METHODSEight healthy men underwent two studies each, in random order, 4–6 weeks apart in which de novo lipogenesis, kinetics of larger VLDL1 TG, and kinetics of VLDL1 and smaller VLDL2 apolipoprotein (apo)B100 and B48 were studied using established stable isotope enrichment methods. Subjects were studied in the constant fed state under conditions of a pancreatic clamp (with infusion of somatostatin, insulin, and growth hormone) at either basal glucagon (BG study, 64.5 ± 2.1 pg/mL) or hyperglucagonemia (high glucagon [HG] study, 183.2 ± 5.1 pg/mL).RESULTSThere were no significant differences in plasma concentration of VLDL1 or VLDL2 TG, apoB100 or apoB48 between BG and HG studies. There was, however, lower (P < 0.05) VLDL1 apoB100 fractional catabolic rate (−39%) and production rate (−30%) in HG versus BG, but no difference in de novo lipogenesis or TG turnover, and glucagon had no effect on intestinal (B48-containing) lipoprotein metabolism.CONCLUSIONSGlucagon acutely regulates hepatic but not intestinal lipoprotein particle metabolism in humans both by decreasing hepatic lipoprotein particle production as well as by inhibiting particle clearance, with no net effect on particle concentration.