TABLE 3.

Proposed mechanisms by which individuals with low-grade inflammation or insulin resistance could have a blunted lipid and lipoprotein response to cholesterol-lowering diets¹

Inflammation blunts cholesterol efflux:

Modulates SCD1, ABCA1 and ABCG1, and SR-B1

Induces HDL-cholesterol remodeling

Inflammation alters genes involved in endogenous cholesterol synthesis and cholesterol uptake:

Reduces LDL-cholesterol clearance by upregulating PCSK9 expression

Alters LDL-R expression by modulating transcription factors from the SREBP and HNF1α families

Insulin and inflammatory cytokines increase PCSK9 production by SOCS3-dependent pathways and upregulate de novo lipogenesis:

Insulin induces SOCS3, which upregulates SREBP-1c expression and enhances fatty acid synthesis

Proinflammatory cytokines increase SOCS3 protein expression; and SOCS3 is required for the TNF-α induction of PCSK9

¹ABC, ATP-binding cassette transporter; HNF1α, hepatocyte nuclear factor-1α; LDL-R, LDL receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SCD1, stearoyl CoA desaturase 1; SOCS3, suppressor of cytokine signaling-3; SR-B1, scavenger receptor class B type; SREBP, sterol regulatory element binding protein.