Vous êtes sur la page 1sur 2

The Ameliorative Action of Peptides on Lipid Metabolism 10.4.

1 Hypotriglyceridemic Action of Peptides In recent years, it has been reported that the oligopeptides have a hypotriglyceridemic property by suitable protease digestion of various edible proteins, such as globin, soy protein, and casein. Globin digest (GD), prepared from globin by acidic protease treatment, suppressed the elevation of the serum triglyceride level in not only total but also chylomicron fraction after oral administration of olive oil. By screening with this lowering activity, it was reported that Val-Val-Tyr-Pro (VVYP) would be the most effective constituent having a hypotriglyceridemic action in GD (Kagawa et al. 1996). Furthermore, the administration of GD caused a more prominent activation of the hepatic triglyceride lipase (HTGL) and an increase in hepatic free fatty acid (FFA) concentration in the early phase after the administration of fat. From these results, it could be elucidated that GD, and also VVYP, inhibited fat absorption from the digestive tract and enhanced the activity of HTGL, thereby causing a more rapid clearance of dietary hypertriglyceridemia. They also reported the suppressive effect of GD on postprandial hyperlipidemia in male volunteers (Kagawa et al. 1998). 10.4.2 Antiobesity Action of Peptides An antiobesity therapy based on targeted induction of apoptosis in the vasculature of adipose tissue has been reported (Kolonin et al. 2004). They used an in vivo phage display to isolate a peptide motif (sequence CKGGRAKDC) that homes white fat vasculature. They also showed that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and establishes prohibitin as a vascular marker of adipose tissue. Targeting a proapoptotic peptide, CKGGRAKDC-GG-KLAKLAKKLAKLAK, to establish prohibitin in the adipose vasculature caused ablation of white fat. 10.4.3 Antiatherogenic Action of Peptides Apolipoprotein A-I (apoA-I) is the main protein component in high-density lipoprotein (HDL). The beneficial effects of HDL have largely been attributed to its major protein, apoA-I. Decades of research have gone into the synthesis of apoA-I mimetic peptides. There has been a long search for peptides smaller than apoA-I, but with many of the properties of apoA-I. The structural requirements for the antioxidative and anti-inflammatory properties of apoA-I mimetic peptides have recently been reviewed (Van Lenten et al. 2009). The 4F (DWFKAFYDKVAEKFKEAF) peptides, L-4F and D-4F, are apoA-I mimetics that demonstrate prominent anti-inflammatory properties in vitro and in animal models (Van Lenten et al. 2009. The 4F peptide is an anti-inflammatory, apoA-I mimetic peptide that is active in vivo at nanomolar concentrations in the presence of a large molar excess of apoA-I. The physiological concentrations (35 M) of human apoA-I did not inhibit the production of LDL-induced monocyte chemotactic activity by human aortic endothelial cell cultures, but adding nanomolar concentrations of 4F in the presence of 35 M apoA-I significantly reduced this inflammatory response. The anti-inflammatory 4F peptide bound the oxidized lipids with much higher affinity than did apoA-I. Initially, they examined the binding of PAPC (1-palmitoyl-2-arachidonoyl-sn-glycero-3phosphatidylcholine) and observed that its oxidized products bound the 4F peptide with an affinity that was 46 orders of magnitude higher than that of apoA-I. Meanwhile, a peptide containing only four amino acid residues (KRES), which is too small to form an amphipathic helix, reduced lipoprotein lipid hydroperoxides (LOOH), increased

paraoxonase activity, increased plasma HDL-cholesterol levels, rendered HDL anti-inflammatory, and reduced atherosclerosis in apoE null mice (Navab et al. 2006). Changing the order of two amino acids (from KRES to KERS) resulted in the loss of all biological activity. The solubility in ethyl acetate and the interaction with lipids indicated significant differences between KRES and KERS. Negative stain electron microscopy showed that KRES formed organized peptide lipid structures, whereas KERS did not. After oral administration, KRES and FREL were found to be associated with HDL, whereas KERS was not. They concluded that the ability of peptides to interact with lipids, remove LOOH, and activate antioxidant enzymes associated with HDL determines their antiinflammatory and antiatherogenic properties regardless of their ability to form amphipathic helixes. 10.4.4 Inhibitory Action of Fatty Acid Synthase by Peptides Fatty acid synthase (FAS, EC 3.2.1.85) is a multicomponent enzyme that catalyzes the biosynthesis of long-chain fatty acids through an NADPH-dependent cyclic reaction (Chakravarty et al. 2004). FAS is homodimeric, and each polypeptide chain carries seven catalytic domains integrating all the steps needed for fatty acid synthesis (Smith and Tsai 2007; Maier, Jenni, and Ben 2006). The discovery and development of pharmacological FAS inhibitors promise the prevention of obesity, related metabolic disorders, and cancer (Sheng, Niu, and Sun 2009; Ronnett et al. 2005). The inhibition of FAS in the central nervous system markedly reduces food intake and body weight in animals (Loftus et al. 2000). The inhibition of FAS in the hypothalamus and pancreatic b cells protects mice against high-fat dietinduced metabolic syndrome (Chakravarthy, Zhu, and Yin 2009). Martinez-Villaluenga et al. (2010) reported that three peptides derived from -conglycinin (KNPQLR, EITPEKNPQLR, and RKQEEDEDEEQQRE) inhibited FAS. The biological activity of these peptides was confirmed by their inhibitory activity against purified chicken FAS and a high correlation (r = 0.7) with lipid accumulation in the 3T3-L1 adipocytes. The FAS inhibitory potency of soy peptides also correlated with their molecular mass, their pI value, and the number of negatively charged and hydrophilic residues. Molecular modeling predicted that the large FAS inhibitory peptides (EITPEKNPQLR and RKQEEDEDEEQQRE) bond to the thioesterase domain of human FAS with lower interaction energies than classical thioesterase inhibitors (Orlistat). Docking studies suggested that soy peptides blocked the active site through interactions within the catalytic triad, the interface cavity, and the hydrophobic groove in the human FAS thioesterase domain. FAS thioesterase inhibitory activities displayed by the synthetic soy peptides EITPEKNPQLR and RKQEEDEDEEQQRE were higher than C75 but lower than Orlistat.