T2D PBMC Cholesterol Efflux and Scavenger Receptors

Fakhoury et al. 2022 measured mRNA expression of cholesterol efflux proteins and scavenger receptors in PBMCs from T2D patients, revealing a disrupted lipid-handling profile in circulating immune cells.

Cholesterol Efflux in T2D PBMCs

Protein	T2D vs. Non-Diabetic	Metformin Effect
ABCA1	Increased	No significant change
ABCG1	Decreased	No significant change
CYP27A (sterol 27-hydroxylase)	Decreased	Increased

• The ABCA1-high/ABCG1-low dichotomy is notable: ABCA1 promotes unidirectional cholesterol efflux to apoA-I and HDL particles; ABCG1 promotes LPL-dependent triglyceride storage in adipocytes and modulates ATM cholesterol content. ¹
• ABCG1 has been shown to be reduced in metabolic syndrome patients, and ABCG1 regulates the M1/M2 ratio in adipose tissue macrophages during obesity and weight loss. ¹
• ABCA1 stimulates monocyte production, potentially exacerbating inflamed-tissue macrophage accumulation — the increase in T2D may reflect this mechanism. ¹
• The M1 macrophage phenotype has been shown to express high ABCA1; the ABCA1 increase in T2D PBMCs is consistent with a partial M1-like component in the MMe profile. ¹

Scavenger Receptors in T2D PBMCs

Receptor	T2D vs. Non-Diabetic	Metformin Effect
SR-A1	Increased	Non-significant decrease
LOX-1	Non-significant decrease	Increased
CXCL16	Non-significant increase	Increased

• SR-A1 (major scavenger receptor for modified lipid uptake) was increased in T2D PBMCs, paralleling increased CD36 expression reported in T2D monocytes. ¹
• Adipose tissue scavenger receptors (SR-A, LOX-1) are strongly associated with insulin resistance. ¹
• Metformin’s significant increase of LOX-1 and CXCL16 in the T2D-on-metformin group is interpreted as an athero-protective effect. CXCL16−/−/LDLR−/− mice show accelerated atherosclerosis, suggesting CXCL16 has a protective role. ¹
• CXCL16 serves both as an adhesion molecule (CXCR6 ligand) and as a scavenger receptor for oxLDL. ¹

Relevance To The Paper

• The disrupted cholesterol efflux profile (ABCA1 up, ABCG1 down, CYP27A down) provides an additional molecular axis — beyond inflammatory markers — for characterizing T2D PBMC dysregulation. ²
• Metformin’s differential effects on scavenger receptors (raising LOX-1, CXCL16, and CYP27A but not ABCA1 or ABCG1) suggests medication-specific remodeling of PBMC lipid handling, which should be tracked as a potential confound in PBMC studies. ²

Sources

• Fakhoury et al. 2022

Footnotes

1. extracted; from Fakhoury et al. 2022 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

2. inferred; lipid-handling interpretation and medication-confounding discussion ↩ ↩²