Cholesterol regulation of receptor‐interacting protein 140 via microRNA‐33 in inflammatory cytokine production

Abstract

Receptor interacting protein 140 (RIP140) is a nuclear receptor coregulator that affects a wide spectrum of biological processes. It is unclear whether and how the expression level of RIP140 can be modulated and whether RIP140 is involved in inflammatory diseases. Here, we examine how intracellular cholesterol regulates RIP140 expression, and we evaluate the effect of RIP140 expression on macrophage proinflammatory potential. Macrophages treated with modified low-density lipoprotein express higher RIP140 mRNA and protein levels. Consistently, simvastatin reduces RIP140 levels, which can be reversed by mevalonate. Moreover, a high-fat diet elevates RIP140 but lowers miR-33 levels in peritoneal macrophages, and increases the production of IL-1β and TNF-α in macrophages. Mechanistically, miR-33 targets RIP140 mRNA by recognizing its target located in a highly conserved sequence of the 3'-untranslated region (3'-UTR) of RIP140 mRNA. Consequentially, miR-33 reduces RIP140 coactivator activity for NF-κB, which is supported by the reduction in NF-κB reporter activity and the inflammatory potential in macrophages. This study uncovers a cholesterol-miR-33-RIP140 regulatory pathway that modulates the proinflammatory potential in macrophages in response to an alteration in the intracellular cholesterol status, and identifies RIP140 as a direct target of miR-33 that mediates simvastatin-triggered anti-inflammation.

MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

“…For example, miR-33 was recently reported to repress the tumor suppressor p53 (50); we and others have reported that p53-deficient mice display enhanced proinflammatory gene expression in response to LPS due to derepression of NF-B (51,52). Alternatively, the potential for miR-33 to suppress inflammation in some contexts is also suggested by a recent report that miR-33 represses the NF-B co-activator receptor-interacting protein-140 (53).…”

A Regulatory Role for MicroRNA 33* in Controlling Lipid Metabolism Gene Expression

“…Similarly, when Srebp-1c is induced during hyperinsulinemia or insulin resistance, miR-33b is cotranscribed and works to reduce cellular fatty acid oxidation by targeting carnitine O-octanoyltransferase (CROT), carnitine palmitoyltransferase 1A (CPT1a), hydroxyacyl coenzyme A (hydroxyacyl-CoA) dehydrogenase subunit beta (HADHB), and AMP kinase subunit alpha (AMPK␣), as well as insulin signaling, by targeting insulin receptor substrate 2 (IRS2) and sirtuin 6 (SIRT6) (23,24). In addition, we and others have recently shown that miR-33 contributes to the regulation of cholesterol and fatty acid homeostasis by targeting key transcriptional regulators of lipid metabolism, including steroid receptor coactivator 1 (SRC1), steroid receptor coactivator 3 (SRC3), nuclear transcription factor Y, gamma (NFYC), and nuclear receptor-interacting protein 1 (RIP140) (25).…”

M1-M2 balancing act in white adipose tissue browning – a new role for RIP140

“…Supporting this finding, we previously found that the level of RIP140 is dramatically elevated in macrophages of HDF-induced obese mice. 14,19 Thus, HFD-associated obesity could involve elevating RIP140 expression, which would induce not only M1 monocyte recruitment but also M1 ATM polarization (or repress M2 ATM polarization). Conversely, reducing RIP140 levels in monocytes would reduce M1 monocyte recruitment and M1 ATM polarization (or derepress M2 ATM polarization).…”