Meaning of familial hypercholesterolemia in lipid metabolism In human genetics and metabolism, familial hypercholesterolemia (a form of cholesterolemia) most commonly results from:

Introduction / Context:
Familial hypercholesterolemia (FH) is a classic autosomal disorder causing markedly elevated LDL cholesterol and premature atherosclerosis. The prototypical molecular lesion involves the LDL receptor pathway. Recognizing this mechanism is essential for interpreting lipid profiles and therapy choices (statins, PCSK9 inhibitors).

Given Data / Assumptions:

• FH leads to high plasma LDL cholesterol from birth.
• LDL receptor (LDLR) mediates endocytosis of LDL particles via ApoB100.
• Alternative, rarer causes exist (ApoB100 mutations, PCSK9 gain of function), but LDLR deficiency is most common.

Concept / Approach:

Defective or absent LDL receptors reduce hepatic clearance of LDL, increasing circulating LDL particle concentration. Elevated LDL promotes cholesterol deposition in tendons (xanthomas) and arteries. Targeted therapies upregulate LDLR or reduce LDL production to mitigate risk.

Step-by-Step Solution:

Verification / Alternative check:

Cellular studies show reduced LDL uptake in FH fibroblasts; genetic testing frequently reveals LDLR mutations. PCSK9 gain of function also reduces receptor levels, reinforcing LDLR centrality.

Why Other Options Are Wrong:

HDL receptor (SR B1) defects are not the canonical cause of FH. Dietary sensitivity alone cannot explain severe, lifelong hypercholesterolemia. ApoB48 absence pertains to chylomicron assembly, not the classic FH phenotype.

Common Pitfalls:

Equating general high cholesterol with FH or assuming diet alone causes extreme LDL elevations found in FH.

Final Answer:

Lack of functional LDL receptors leading to impaired LDL clearance