A 58-year-old man with poorly controlled hyperlipidaemia and smoking history presents with acute anterior wall myocardial infarction. Coronary angiography reveals plaque rupture with superimposed thrombosis in the left anterior descending artery. Histopathological examination of the ruptured plaque shows a thin fibrous cap overlying a large necrotic lipid core, with abundant lipid-laden macrophages (marked **B** in the diagram). These foam cells accumulated lipid through a mechanism that differs fundamentally from the classical LDL receptor pathway. Which of the following best explains why foam cells in atherosclerotic plaques continue to accumulate cholesterol despite high intracellular cholesterol levels?

Explanation

## Why Scavenger receptors (CD36, SR-A) lack feedback inhibition is right Foam cells are macrophages that engulf oxidized LDL (oxLDL) via scavenger receptors—primarily CD36 and SR-A—which are fundamentally different from the classical LDL receptor (LDLR). The critical distinction is that scavenger receptors are NOT downregulated by intracellular cholesterol accumulation, unlike LDLR, which undergoes feedback inhibition when cellular cholesterol is high. This unregulated uptake allows macrophages to become progressively lipid-laden despite cholesterol overload, forming foam cells. This mechanism is central to atherosclerotic plaque formation and explains why foam cells contribute to plaque vulnerability through continued lipid accumulation and secretion of pro-inflammatory mediators and metalloproteinases that weaken the fibrous cap (Robbins 10e Ch 11; Harrison 21e Ch 268). ## Why each distractor is wrong - **Classical LDL receptors on macrophages are upregulated in response to oxidized LDL**: This is backwards. LDLR expression is downregulated by intracellular cholesterol via SREBP-mediated feedback. Scavenger receptors, not LDLR, are the primary pathway in foam cell formation, and they lack this feedback control. - **Foam cells express increased numbers of LDLR resistant to PCSK9-mediated degradation**: LDLR is not the dominant receptor in foam cell formation. Moreover, PCSK9 inhibition would reduce atherosclerosis risk, not promote foam cell accumulation. This confuses the classical cholesterol homeostasis pathway with the pathological scavenger receptor pathway. - **Macrophages preferentially metabolize oxidized LDL through lysosomal lipase, preventing cholesterol esterification**: While lysosomal lipase does hydrolyze cholesteryl esters in macrophages, the problem is not prevention of esterification—it is the continued unregulated uptake of oxLDL via scavenger receptors. Cholesterol esterification actually occurs and contributes to lipid accumulation in foam cells. **High-Yield:** Scavenger receptors (CD36, SR-A) on macrophages lack feedback inhibition by intracellular cholesterol, unlike LDLR—this is why macrophages become foam cells and why vulnerable plaques rupture, causing acute MI. [cite: Robbins 10e Ch 11; Harrison 21e Ch 268]