Cholesterol Biosynthesis—Primary Site of de novo Synthesis In humans, which organ is the principal site for de novo cholesterol synthesis under normal physiological conditions?

Introduction / Context:
Cholesterol is a vital lipid serving as a membrane component and precursor for bile acids, steroid hormones, and vitamin D. While many tissues can synthesize cholesterol, one organ plays the dominant role in overall production and distribution via lipoproteins.

Given Data / Assumptions:

• Pathway: acetyl-CoA → HMG-CoA → mevalonate → isoprenoids → squalene → cholesterol.
• Rate-limiting enzyme: HMG-CoA reductase (target of statins).
• Need for systemic export via very-low-density lipoproteins (VLDL).

Concept / Approach:
The liver is the central metabolic hub for lipid synthesis and trafficking. It expresses high levels of HMG-CoA reductase and packages cholesterol into lipoproteins for delivery to peripheral tissues. Although intestine and other tissues contribute, hepatic synthesis is predominant in whole-body balance.

Step-by-Step Solution:

Verification / Alternative check:
Clinical pharmacology: statins primarily affect hepatic cholesterol synthesis, lowering LDL-cholesterol via upregulated LDL receptors—evidence of the liver’s central role.

Why Other Options Are Wrong:

• Pancreas/kidney: can synthesize some cholesterol but are not the main systemic source.
• Intestine: synthesizes and absorbs cholesterol but is not the principal producer in most contexts.
• Cell membrane: a structure, not an organ capable of de novo synthesis.

Common Pitfalls:
Equating “site of cholesterol” (membranes) with “site of synthesis” (hepatocytes and other cells).

Final Answer:
Liver