Quartet of APOCs and the Different Roles They Play in Diabetes

Abstract

APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density lipoprotein, respectively. The 4 smaller APOCs (APOC1, APOC2, APOC3, and APOC4) are exchangeable apolipoproteins; they are readily transferred among high-density lipoproteins and APOB-containing lipoproteins. The APOCs regulate plasma triglyceride and cholesterol levels by modulating substrate availability and activities of enzymes interacting with lipoproteins and by interfering with APOB-containing lipoprotein uptake through hepatic receptors. Of the 4 APOCs, APOC3 has been best studied in relation to diabetes. Elevated serum APOC3 levels predict incident cardiovascular disease and progression of kidney disease in people with type 1 diabetes. Insulin suppresses APOC3 levels, and accordingly, elevated APOC3 levels associated with insulin deficiency and insulin resistance. Mechanistic studies in a mouse model of type 1 diabetes have demonstrated that APOC3 acts in the causal pathway of diabetes-accelerated atherosclerosis. The mechanism is likely due to the ability of APOC3 to slow the clearance of triglyceride-rich lipoproteins and their remnants, thereby causing an increased accumulation of atherogenic lipoprotein remnants in lesions of atherosclerosis. Less is known about the roles of APOC1, APOC2, and APOC4 in diabetes.

Proteomic and Lipidomic Plasma Evaluations Reveal Biomarkers for Domoic Acid Toxicosis in California Sea Lions

“…For example, APOC1 and APOC4 had lower abundances in the DAT group and are thought to be involved in triglyceride metabolism, although the function of endogenous APOC4 is not completely known. 31,32 APOC2 was also not statistically significant but trended higher in the DAT group, and high APOC2 levels have been associated with downregulation of plasma TGs in humans. 32 Since this study size is small, the trends in these non-significant apolipoproteins are also notable.…”

“…31,32 APOC2 was also not statistically significant but trended higher in the DAT group, and high APOC2 levels have been associated with downregulation of plasma TGs in humans. 32 Since this study size is small, the trends in these non-significant apolipoproteins are also notable.…”

A targeted proteomics method for quantifying plasma apolipoprotein kinetics in individual mice using stable isotope labeling

“…The similar FCRs of APOC3 and APOC2 are also consistent with previous studies in humans ( 29 , 30 ). All APOCs are exchangeable apolipoproteins, moving readily between APOB-containing lipoproteins and HDL ( 31 ). Indeed, human studies have shown that the FCRs for APOC3 associated with APOB lipoproteins versus HDL are very similar and that it therefore is as informative to evaluate APOC3 overall FCRs in plasma ( 29 , 30 ).…”

Apolipoprotein C3: form begets function

“…APOC3 has two mechanisms of action in triglyceride and cholesterol metabolism, both related to slower clearance of TRLs ( 16 , 42 ). Although APOC3 was found to increase VLDL production and APOB secretion in one study ( 43 ), later studies showed that endogenous APOC3 does not act through increasing VLDL production ( 44 , 45 , 46 , 47 ).…”

“…Cardiovascular outcome trials that include subjects with and without diabetes would be the next important step ( 80 ). Including participants with diabetes would be important also because there are inconclusive indications that APOC3 inhibition could improve insulin sensitivity ( 42 ). However, there are several important considerations.…”