Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III

• Published in: Journal of lipid research 1992-07, Vol.33 (7), p.995-1003
• Main Authors: McConathy, WJ, Gesquiere, JC, Bass, H, Tartar, A, Fruchart, J C, Wang, CS
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Apolipoprotein C-III; Apolipoproteins C - blood; Apolipoproteins C - chemical synthesis; Apolipoproteins C - pharmacology; Biological and medical sciences; Catalysis; Cyanogen Bromide; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases; Kinetics; Lipoprotein Lipase - antagonists & inhibitors; Lipoproteins, VLDL - metabolism; Molecular Sequence Data
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1016/S0022-2275(20)41415-4

In this study we have examined effects of synthetic polypeptide fragments of apoC-III on the kinetic properties of lipoprotein lipase (LPL) activity. Based on the loss of 79% of LPL-inhibitory activity after CNBr cleavage at the N-terminal portion of apoC-III and a systematic search for synthetic peptides with LPL-inhibitory activity spanning the apoC-III sequence, we concluded that the N-terminal domain is the most important in the modulation of LPL activity. In addition, there are multiple attachment sites in apoC-III for its interaction with LPL and these sites reside in the hydrophilic sequences of apoC-III. Probably for this reason the intact apo-CIII exhibited higher inhibitory potential than its peptide components. Based on the deduced inhibition constants derived for the synthetic apoC-III1-79 we concluded that apoC-III is likely to exhibit a physiological role in regulating LPL activity since the derived dissociation constants for the LPL-apoC-III interaction are within the physiological concentration range of plasma apoC-III. In addition, as the synthetic apoC-III1-79 lacks the carbohydrate moiety, we also concluded that the presence of the oligosaccharide in native apoC-III is not essential for its inhibitory activity on LPL. The fact that the I50 (concentration for inhibition of LPL at 50% activity) decreases for apoC-III-1 when assayed in the presence of apoC-II indicated that the activator actually caused an increased affinity between LPL and apoC-III and demonstrated that apoC-III does not compete for the activator site of apoC-II.