Biochemistry

Lipoproteins are organized with a hydrophobic lipid core (cholesterol esters and triglycerides) surrounded by a hydrophilic shell of proteins, free cholesterol, and phospholipids.

Gaucher disease is caused by deficiency of glucocerebrosidase (beta-glucosidase), leading to accumulation of glucocerebroside in macrophages of the reticuloendothelial system. Type 1 is the non-neuronopathic form with hepatosplenomegaly; Type 2 and 3 involve CNS involvement.

Dietary cholesterol intake inversely affects endogenous cholesterol synthesis through feedback inhibition of HMG-CoA reductase. However, saturated and trans fats have a greater impact on LDL cholesterol than dietary cholesterol itself. Genetic factors are the primary determinant of serum cholesterol.

Sterol 7-alpha-hydroxylase catalyzes the first committed step of bile acid synthesis, forming 7-alpha-hydroxycholesterol from cholesterol. This is the rate-limiting step and is regulated by feedback inhibition by bile acids and activation by cholesterol.

Severe hypertriglyceridemia with eruptive xanthomas and lipemia retinalis indicates predominantly elevated chylomicrons and/or VLDL. This is seen in Type I (lipoprotein lipase deficiency), Type IV (VLDL overproduction), or Type V hyperlipoproteinemia.

VLDL triglyceride content increases during increased hepatic triglyceride synthesis (fed state, fatty liver). HDL is the smallest and most dense; chylomicrons have the lowest protein percentage; LDL particle size varies (pattern A = large, pattern B = small and dense).

The E4/E4 genotype carries the highest genetic risk for late-onset Alzheimer's disease. ApoE4 is less efficient at clearing amyloid-beta and is associated with increased neuroinflammation. E4 carriers show earlier cognitive decline compared to E2 and E3 carriers.

Niemann-Pick disease Type A is caused by deficiency of acid sphingomyelinase, leading to accumulation of sphingomyelin and cholesterol in lysosomes of various tissues, particularly the CNS, liver, and spleen. It presents with hepatosplenomegaly and neurological deterioration.

Palmitate (16 carbons) undergoes 7 cycles of beta-oxidation (n/2 - 1), each producing one acetyl-CoA. The final cycle releases 2 acetyl-CoA molecules, totaling 8 acetyl-CoA. Each 2-carbon unit is released as acetyl-CoA.

Familial hypercholesterolemia results from defective LDL receptors, leading to severely elevated LDL cholesterol (200-1000 mg/dL). This causes premature atherosclerosis, xanthomas, and corneal arcus. The defect prevents normal clearance of LDL from circulation.