Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E.

Abstract

The mechanism of apolipoprotein (apo) CIII-induced hypertriglyceridemia remains uncertain. We crossed apoCIII transgenic and apoE gene knockout (apoE 0 ) mice, and observed severe hypertriglyceridemia with plasma triglyceride levels of 4,521 Ϯ 6,394 mg/dl vs. 423 Ϯ 106 mg/dl in apoE 0 mice, P Ͻ 0.00001 for log(triglycerides [TG]). Cholesterols were 1,181 Ϯ 487 mg/dl vs. 658 Ϯ 151 mg/dl, P Ͻ 0.0001. Lipoprotein fractionation showed a marked increase in triglyceride-enriched chylomicrons ϩ VLDL. This increase was limited to the lowest density (chylomicrons and S f 100-400) subfractions. Intermediate density lipoproteins (IDL) ϩ LDL increased moderately, and HDL decreased. There was no significant increase in triglyceride production in apoCIII transgenic/apoE 0 mice. The clearance of VLDL triglycerides, however, was significantly decreased. Lipoprotein lipase in postheparin plasma was elevated, but activation studies suggested LPL inhibition by both apoCIII transgenic and apoCIII transgenic/apoE 0 plasma. ApoCIII overexpression also produced a marked decrease in VLDL glycosaminoglycan binding which was independent of apoE. The predominant mechanism of apoCIII-induced hypertriglyceridemia appears to be decreased lipolysis at the cell surface. The altered lipoprotein profile that was produced also allowed us to address the question of the direct atherogenicity of chylomicrons and large VLDL. Quantitative arteriosclerosis studies showed identical results in both apoCIII transgenic/apoE 0 and apoE 0 mice, supporting the view that very large triglyceride-enriched particles are not directly atherogenic. ( J. Clin. Invest. 1997. 99:2672-2681.)

Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins

“…It is interesting that IDFP-induced increases in plasma TG values in ϩ/ϩ mice reached levels similar to those in apoEϪ/Ϫ mice. Despite high basal TG levels, apoEϪ/Ϫ mice can undergo still further increases in TG as a result of enhanced secretion or impaired lipolytic clearance (34,35). As shown here for IDFP-treated wild-type mice, apoEϪ/Ϫ mice have similarly high concentrations of apoAI in native apoB-containing lipoproteins and accumulation in plasma of apoB48 particles that rely solely on apoE for receptor-mediated clearance.…”

The genetic background modifies the effects of the obesity mutation, ‘fatty’, on apolipoprotein gene regulation in rat liver

“…8±11 ApoC-III, a component of triglyceride-rich lipoproteins and HDL, retards the catabolism of triglyceride-rich particles, and plays a role in the pathogenesis of some forms of hypertriglyceridaemia. 12 In humans, obesity is associated with high apoC-III, but low plasma apoA-I concentrations in plasma. 13,14 Homozygosity for the missense mutation`fatty' ( fa), Glu269Pro, in the leptin receptor gene causes the obese phenotype in ( faafa) Zucker fatty rats.…”

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

“…The general consensus is that apoC-III increases plasma triglycerides by affecting the function of LPL, but the mechanism for this inhibitory effect is not yet resolved. In addition, apoC-III has been reported to interfere with VLDL assembly and secretion (14), binding of lipoproteins to glycosaminoglycans (15), and lipoprotein remnant clearance by receptor-mediated endocytosis (16).…”