The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

Abstract

Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-a-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.

CD301b + Mononuclear Phagocytes Maintain Positive Energy Balance through Secretion of Resistin-like Molecule Alpha

“…Retnla −/− mice show faster glucose clearance in GTT in mice with dextran sodium sulfate-induced colitis (Munitz et al, 2009). Furthermore, RELMα deficiency in Ldlr − / − atherosclerotic mice results in hypercholesterolemia, while its overexpression in WT animals reduces serum cholesterol and directly induces bile acid synthases Cyp7a1 and Cyp8b1 in the liver (Lee et al, 2014). Our results of the elevated serum cholesterol and reduced hepatic Cyp8b1 expression in CD301b + MNP-depleted mice are thus consistent with these studies.…”

Lens ER-stress response during cataract development in Mip-mutant mice

“…Cox6a2 is a nuclear gene that encodes one of 13 subunits of the mitochondrial cytochrome c oxidase complex that if deficient in mice results in ROS overproduction in skeletal muscle (70). Retnla encodes an adipokine with cholesterol catabolism properties (71) raising the possibility of an anti-inflammatory-like response during cataract development in the Lop/+ lens. Sqstm1 encodes a stress-induced scaffold protein (p62) with multiple domains that act as a signaling hub for diverse cellular events including, NF-kB activation, mTORC1 activation, selective autophagy, and Nrf2 signaling (72).…”

Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

“…New studies have identified a critical metabolic function for RELMα in protection against atherosclerosis in both high fat diet fed mice and LDL receptor deficient mice [84]. Mice lacking the LDL receptor ( ldlr −/− ) cannot efficiently remove circulating LDL, leading to increased formation of atherosclerotic plaques in the context of high fat diet.…”