👤 Margaret R Diffenderfer

Decreased serum high-density-lipoprotein-cholesterol (HDL-C), HDL particles, and cell-cholesterol-efflux-capacity have all been associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. Our goals are to summarize recent findings with regard to these topics. Apolipoprotein (apo) A1 containing HDL particles have been characterized by two-dimensional gel electrophoresis and apoA1 immunoblotting and range from very small preβ-1 HDL, small α-4 HDL, medium α-3 HDL to large and very large α-2 and α-1 HDL. Preβ-1 HDL are most efficient in serving as acceptors of free cholesterol and phospholipid from cells via ATP binding cassette transporter A1, while α-2 and α-1 HDL are most efficient in delivering cholesteryl-ester to the liver via scavenger receptor-B1 or to triglyceride-rich lipoproteins (TRL) in exchange for triglycerides via cholesteryl ester transfer protein (CETP). Recent research on the relationships of the lipid and protein composition, function, metabolism and levels of HDL particles to ASCVD risk will be reviewed, as will advances in potential therapeutic options. HDL particles are by far the most abundant lipoproteins in plasma and contain 110 proteins involved in lipid metabolism and immune function. ApoA1, apoA2, and all lipid classes are found in all HDL particles. Low levels of large and very large α-HDL and increased levels of very small preβ-1 HDL have been associated with increased ASCVD risk. The best therapeutic options for ASCVD risk reduction in patients with low HDL-C is optimizing other risk factors including low-density-lipoprotein (LDL)-C, small-dense LDL-C, plasma-glucose, body-mass-index, blood pressure, and the promotion of smoking cessation. Show less

Triglyceride (TG) concentrations >2000 mg/dL are extremely elevated and increase the risk of pancreatitis. We characterized five cases and two kindreds and ascertained prevalence in a reference laboratory population. Plasma lipids and DNA sequences of LPL, GPIHBP1, APOA5, APOC2, and LMF1 were determined in cases and two kindreds. Hypertriglyceridemia prevalence was assessed in 440,240 subjects. Case 1 (female, age 28 years) had TG concentrations >2000 mg/dL and pancreatitis since infancy. She responded to diet and medium-chain triglycerides, but not medications. During two pregnancies, she required plasma exchange for TG control. She was a compound heterozygote for a p.G236Gfs*15 deletion and a p.G215E missense mutation at LPL, as was one sister with hypertriglyceridemia and pancreatitis during pregnancy. Her father was heterozygous for the deletion and had hypertriglyceridemia and recurrent pancreatitis. Other family members had either the missense mutation or the deletion, and had hypertriglyceridemia but no pancreatitis. In kindred 2, three preschool children had severe hypertriglyceridemia and were homozygous for a GPIHBP1 p.T108R missense mutation. Case 5 (male, age 43 years) presented with pancreatitis and TG levels >5000 mg/dL and had heterozygous GPIHBP1 p.G175R and APOC2 intron 2-4G>C mutations. On diet, fenofibrate, fish oil, and atorvastatin, his TG concentration was 2526 mg/dL, but normalized to <100 mg/dL with added pioglitazone. In our population study, 60 subjects (0.014%) of 440,240 had TG concentrations >2000 mg/dL, and 66.7% were diabetic and had elevated insulin levels. Extreme hypertriglyceridemia is rare (0.014%); and during pregnancy, it may require plasma exchange. Show less