Independent regulation of plasma apolipoprotein C-ll

Apolipoproteins C-I1 (apoC-11) and C-111 (apoC-111) are distributed among all the major lipoprotein classes, particularly very low density (VLDL) and high density lipoproteins (HDL). We have determined concentrations of apoC-I1 and apoC-111 in VLDL and HDL in subjects with a wide range of VLDL triglyceride and HDL cholesterol levels, and correlated these levels with fractional catabolic rates (FCR) of VLDL triglyceride and HDL apolipoprotein A-I (apoA-I). Both apoC-I1 and apoC-111 levels increased in VLDL as VLDL apolipoprotein B (apoB) and triglyceride levels rose. The rate of rise of VLDL apoC-111, however, was approximately 3 times greater than that of apoC-11, and positive correlations were present between the ratio of VLDL apoC-III/apoC-I1 and both VLDL apoB (7 = 0.59; P < 0.01) and VLDL triglyceride (7 = 0.70; P < 0.005) levels. Univariate analysis demonstrated that the FCR for VLDL triglyceride was inversely related to the ratio of apoC-III/ apoC-I1 in VLDL (7 = -0.58; P < 0.05), although this relationship was not significant in a multivariate analysis. In HDL, concentrations of apoC-111 and apoA-I were correlated (7 = 0.73; P < 0.005) while no correlation was observed between apoC-I1 and a p d I levels. Univariate analyses of HDL variables revealed inverse correlations between the concentration of apoC-111 and the FCR for apoA-I (7 = -0.67; P < 0.005) and between the ratio of apoC-III/apoA-I and the FCR for a p d I (7 = -0.66; P < 0.005). Multivariate analysis confirmed the latter relationship. These results indicate that concentrations of apoC-I1 and apoC-111 in VLDL and HDL are independently regulated, and support roles for both apolipoproteins as regulators of VLDL triglyceride hydrolysis. Our results suggest that apoC-I11 may also regulate HDL metabolism. -Le, N-A., J. C. Gibson, and H. N. Ginsberg. Independent regulation of plasma apolipoprotein C-I1 and C-I11 concentrations in very low density and high density lipoproteins: implications for the regulation of the catabolism of these lipoproteins. J. Lipid Res. 1988. 29: 669-677. Supplementary key words fractional catabolic rate apoA-I apoB VLDL triglyceride Apolipoprotein C-I1 (apoC-11) and apolipoprotein C-111 (apoC-111) are small proteins with similar molecular weights (approximately 8800), which were first isolated together and characterized by Brown, Levy, and Fredrickson (1). Because of their similar molecular weights, their coincident purification, and the observation that they are both associated to varying degrees with all the major lipoprotein classes, these two apolipoproteins (along with apolipoprotein C-I (apoC-I)) have frequently been portrayed as a family: the “C apolipoproteins.” A variety of in vitro studies have clearly indicated one or more specific functions for both apoC-I1 and apoC-111. The functions of apoC-I have been less well defined. The major role of apoC-I1 appears to be as a necessary activator for lipoprotein lipase (LPL) (2, 3), and its absence from in vitro assay systems containing LPL results in the absence of triglyceride hydrolysis. That this in vitro requirement is physiologically relevant in vivo has been demonstrated by the striking elevations of very low density lipoprotein (VLDL) triglycerides present in individuals who lack apoC-II(4). Serum from these individuals is unable to activate LPL in vitro (5), and infusion of normal plasma (4) or a synthetic fragment of apoC-II(6) into these patients corrects their hypertriglyceridemia. ApoC-I1 may also play an inhibitory role in hepatic uptake of triglyceriderich lipoproteins (7). Several groups have presented evidence that apoC-I11 inhibits the uptake of triglyceride-rich lipoproteins by the liver (7-9). The endocytosis of these triglyceride-rich Abbreviations: FCR, fractional catabolic rate; VLDL, very low density lipoprotein; HDL, high density lipoprotein; LDL, low density lipoprotein, ‘Reprint requests should be addressed to Dr. Ngoc-Anh Le, George Hyman Research Building, Medlantic Research Foundation, 108 Irving Street NW, Washington, DC 20010. *Present address: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY. Journal of Lipid Research Volume 29, 1988 669 by gest, on O cber 8, 2017 w w w .j.org D ow nladed fom lipoproteins by hepatocytes is thought to occur via the interaction of apolipoprotein E (apoE) with a receptor(s) present on these cells (10, ll), and the relative amounts of apoC-I11 and apoE present on a lipoprotein particle may regulate this process (12, 13). ApoC-I11 may also inhibit LPL activity (14, 15), raising the possibility that the apoC-III/C-I1 ratio of a triglyceride-rich lipoprotein plays a critical role in regulating triglyceride hydrolysis. A further role for apoC-I11 in the catabolism of triglyceriderich lipoproteins derives from evidence supporting a role for apoC-I11 as an inhibitor of hepatic triglyceride lipase (HTGL) activity (16). This enzyme appears to be involved in the catabolism of small VLDL and intermediate density lipoproteins (17) and in the regulation of high density lipoprotein (HDL) concentrations (18). Studies of the metabolism of triglyceride-rich lipproteins in two sisters who lack apoC-I11 (and apoA-I) supported the hypothesis that apoC-I11 normally inhibits VLDL triglyceride catabolism in vivo (19). In the present study we have determined the concentration of apoC-I1 and apoC-I11 in VLDL and HDL in a group of subjects with a wide range of plasma VLDL triglyceride and HDL cholesterol levels. The relationship between the levels of these apolipoproteins and both the fractional rates of catabolism (FCR) of VLDL triglyceride and the FCR of HDL apoA-I was also examined. Our results demonstrate that the concentrations of apoC-I1 and apoC-I11 in these two lipoproteins are independently regulated. Hence, the ratio of apoC-I11 to apoC-I1 in VLDL increased significantly concomitant with increasing degrees of hypertriglyceridemia. In addition, the levels of apoC-I11 in HDL correlated with those of apoA-I, while no such correlation existed for apoC-I1 and apoA-I. Finally, the kinetic data suggested that the independent regulation of apoC-I11 and apoC-I1 concentrations may play a role in modulating the metabolism of VLDL and HDL.