Biochemistry

Severe hypertriglyceridemia (>1000 mg/dL) significantly increases the risk of acute pancreatitis due to pancreatic inflammation caused by triglyceride-rich lipoproteins.

Deficiency of lipoprotein lipase or its cofactor apoC-II results in severe hypertriglyceridemia with elevated chylomicrons and VLDL but relatively normal LDL levels.

Tangier disease results from mutations in the ABCA1 gene, which encodes a cholesterol transporter. This leads to severe HDL deficiency and accumulation of cholesterol esters in tissues.

CYP27A1 mutations cause cerebrotendinous xanthomatosis (CTX), characterized by elevated cholestanol and cholestane triol precursors due to impaired side-chain oxidation of cholesterol. This leads to progressive neurological deterioration, cataracts, and diarrhea. Chenodeoxycholic acid therapy is beneficial.

Lipoprotein(a) levels are predominantly determined by genetic variations in the LPA gene, which encodes apolipoprotein(a). Smaller isoforms are associated with higher plasma Lp(a) levels and increased cardiovascular risk, independent of LDL cholesterol levels.

ApoB-48 is the truncated form of apoB synthesized in intestinal enterocytes and is essential for chylomicron assembly and secretion. Its deficiency causes abetalipoproteinemia, characterized by fat malabsorption and severe deficiency of fat-soluble vitamins.

In the fed state, high citrate levels allosterically activate ACC, and insulin signaling causes PKB/Akt to phosphorylate and activate ACC. This promotes fatty acid synthesis. Conversely, AMPK phosphorylation inactivates ACC during energy deprivation.

Sterol 27-hydroxylase catalyzes the side-chain oxidation of cholesterol to form bile acid precursors. Its deficiency or dysfunction leads to cholestanol accumulation and neuropathy. Elevated cholestanol is a characteristic finding in sterol 27-hydroxylase deficiency.

Type III hyperlipoproteinemia results from apoE2 homozygosity combined with another genetic or environmental factor. ApoE2 has reduced affinity for lipoprotein receptors, impairing remnant particle clearance.

OxLDL is recognized by scavenger receptors (SR-A and LOX-1) on macrophages, not by the classical LDL receptor. This leads to unregulated cholesterol uptake and foam cell formation in atherosclerosis.