Macrophage Fatty-acid Synthase Deficiency Decreases Diet-induced Atherosclerosis

Abstract

Fatty acid metabolism is perturbed in atherosclerotic lesions, but whether it affects lesion formation is unknown. To determine whether fatty acid synthesis affects atherosclerosis, we inactivated fatty-acid synthase (FAS) in macrophages of apoEdeficient mice. Serum lipids, body weight, and glucose metabolism were the same in FAS knock-out in macrophages (FASKOM) and control mice, but blood pressure was lower in FASKOM animals. Atherosclerotic extent was decreased 20 -40% in different aortic regions of FASKOM as compared with control mice on Western diets. Foam cell formation was diminished in FASKOM as compared with wild type macrophages due to increased apoAI-specific cholesterol efflux and decreased uptake of oxidized low density lipoprotein. Expression of the anti-atherogenic nuclear receptor liver X receptor ␣ (LXR␣; Nr1h3) and its downstream targets, including Abca1, were increased in FASKOM macrophages, whereas expression of the potentially pro-atherogenic type B scavenger receptor CD36 was decreased. Peroxisome proliferator-activated receptor ␣ (PPAR␣) target gene expression was decreased in FASKOM macrophages. PPAR␣ agonist treatment of FASKOM and wild type macrophages normalized PPAR␣ target gene expression as well as Nr1h3 (LXR␣). Atherosclerotic lesions were more extensive when apoE null mice were transplanted with LXR␣-deficient/FAS-deficient bone marrow as compared with LXR␣-replete/FAS-deficient marrow, consistent with antiatherogenic effects of LXR␣ in the context of FAS deficiency. These results show that macrophage FAS deficiency decreases atherosclerosis through induction of LXR␣ and suggest that FAS, which is induced by LXR␣, may generate regulatory lipids that cause feedback inhibition of LXR␣ in macrophages.

Feasibility of 11C-Acetate PET/CT for Imaging of Fatty Acid Synthesis in the Atherosclerotic Vessel Wall

“…In these knock-out mice, compared with wild-type mice, the extent of atherosclerosis was decreased 20%-40% in different aortic regions, underlining the crucial role of FAS in the development of atherosclerotic plaque (22). In another work, Ecker et al demonstrated that induction of fatty acid synthesis is a key requirement for the development of phagocytic capacity in human monocytes and that suppression of fatty acid synthesis prevents uptake of lipoproteins such as enzymatically modified low-density lipoprotein (21).…”

“…Because of the strong expression of FAS in these cells, considerable interest has been shown in the discovery and development of pharmacologic agents that block FAS activity, such as C75 or cerulenin (36,37). If suitable clinical FAS inhibitors become available, they may also prevent de novo fatty acid synthesis in atherosclerotic plaque (22). The incorporation of 11 C-acetate PET into preclinical models and clinical therapy monitoring studies could provide a promising technology to image fatty acid synthesis or the inhibition of FAS in plaque and could therefore represent a unique opportunity for in vivo target validation.…”

“…Thus, there are dynamic and complex interactions between macrophages and lipids such as fatty acids in atherosclerotic plaque. Consequently, inhibition of macrophage fatty acid synthesis decreases diet-induced atherosclerosis in mice (22). In short, intraplaque fatty acid synthesis contributes to plaque growth and is essential for macrophage-mediated inflammation and therefore functional stability, and massive fatty acid accumulation also decreases the structural stability of the plaque.…”

Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling

“…FAS affects activity of the nuclear receptor PPARα in liver (17,22), brain (46), and macrophages (47), and overexpression of PPARα in skeletal muscle causes insulin resistance and inactivates AMPK (18), which led us to consider PPARα as a mediator of the FASKOS phenotype. However, FAS inactivation in muscle did not affect activity of a PPARα reporter gene, and treatment…”

Skeletal muscle lipid flux: running water carries no poison

“…Skeletal muscle CD36 deficiency decreased PPAR␤/␦ gene expression and mitochondrial fat oxidation (46,82). In nonmuscle tissues, including liver, brain, and macrophages, the lipogenic enzyme FAS regulates PPAR␣-dependent gene expression (12,13,100). FAS in adipose tissue is probably involved in regulation of PPAR␥ activity (71,72,99).…”