Apolipoprotein A-IV (apoA-IV) is a satiation factor that acts in the hypothalamus, however, the intracellular mechanisms responsible for this action are still largely unknown. Here we report that apoA Show more
Apolipoprotein A-IV (apoA-IV) is a satiation factor that acts in the hypothalamus, however, the intracellular mechanisms responsible for this action are still largely unknown. Here we report that apoA-IV treatment elicited a rapid activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway in cultured primary hypothalamic neurons, and this effect was significantly attenuated by pretreatment with LY294002, an inhibitor of the PI3K pathway. To determine if the activation of PI3K is required for apoA-IV's inhibitory effect on food intake, apoA-IV was administered intracerebroventricularly. We found that apoA-IV significantly reduced food intake and activated PI3K signaling in the hypothalamus, and these effects were abolished by icv pre-treatment with LY294002. To identify the distinct brain sites where apoA-IV exerts its anorectic action, apoA-IV was administered into the ventromedial hypothalamus (VMH) through implanted bilateral cannula. At a low dose (0.5 μg), apoA-IV significantly inhibited food intake and activated PI3K signaling pathway in the VMH of lean rats, but not in high-fat diet-induced obese (DIO) rats. These results collectively demonstrate a critical role of the PI3K/Akt pathway in apoA-IV's anorectic action in lean rats and suggest a defective PI3K pathway in the VMH is responsible for the impaired apoA-IV's anorectic action in the DIO animals. Show less
Quantitative and qualitative differences in intralumenal bile acids may affect cholesterol absorption and metabolism. To test this hypothesis, 2 cross-over outpatient studies were conducted in adults Show more
Quantitative and qualitative differences in intralumenal bile acids may affect cholesterol absorption and metabolism. To test this hypothesis, 2 cross-over outpatient studies were conducted in adults with apo-A IV 1/1 or apo-E 3/3 genotypes. Study 1 included 11 subjects 24 to 37 years of age, taking 15 mg/kg/day chenodeoxycholic acid (CDCA) or no bile acid for 20 days while being fed a controlled diet. Study 2 included 9 adults 25 to 38 years of age, taking 15 mg/kg/day deoxycholic acid (DCA) or no bile acid, following the same experimental design and procedures as study 1. CDCA had no effect on plasma lipid concentrations, whereas DCA decreased (P < 0.05) plasma high-density lipoprotein (HDL)-cholesterol and tended to decrease (P = 0.15) low-density lipoprotein (LDL)-cholesterol. CDCA treatment enriched (P < 0.0001) bile with CDCA and increased cholesterol concentration in micelles, whereas meal-stimulated bile acid concentrations were decreased. DCA treatment enriched (P < 0.0001) bile with DCA and tended to increase intralumenal cholesterol solubilized in micelles (P = 0.06). No changes were found in cholesterol absorption, free cholesterol fractional synthetic rate (FSR), or 3-hydroxy-3 methylglutaryl (HMG) CoA reductase and LDL receptor messenger ribonucleic acid (mRNA) levels after CDCA treatment. DCA supplementation tended to decrease cholesterol absorption and reciprocally increase FSR and HMG CoA reductase and LDL receptor mRNA levels. Results of these 2 studies suggest that the solubilization of cholesterol in the intestinal micelles is not a rate-limiting step for its absorption. Show less