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The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very long-chain fatty acids (ELOVLs) in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2−/− mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) in both liver and serum, showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24-carbon precursors for DHA and DPAn-6 formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol-regulatory element binding protein 1c (SREBP-1c), as well as its downstream target genes. Surprisingly, the Elovl2−/− mice were resistant to hepatic steatosis and diet-induced weight gain, implying that hepatic DHA synthesis via ELOVL2, in addition to controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP-1c-independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA.

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Although saturated and monounsaturated very-long-chain fatty acids (VLCFAs) have long been associated with undesirable effects on health, including obesity, heart failure, and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20-C24 saturated and monounsaturated VLCFAs mainly in liver, brown and white adipose tissue, and triglyceride-rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue, and resistance against diet-induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation that is associated with reduced de novo fatty acid synthesis and uptake. As a consequence, the VLDL-triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin, and increased expression of orexigenic peptides in the hypothalamus, the Elovl3(-/-) mice do not compensate by increased food intake. Thus, these results reveal that C20-C22 saturated and monounsaturated VLCFAs produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake, and storage in adipose tissue.

Elongation of very long-chain fatty acids (ELOVL) members were overexpressed in two preadipocyte cell lines, ELOVL2 and ELOVL3 in 3T3-L1 cells, and ELOVL1-3 in F442A cells. Cells overexpressing ELOVL2, whose preferred substrates are arachidonic acid (AA, C20:4nÀ6) and eicosapentaenoic acid (EPA, C20:5nÀ3), showed an enhanced triacylglycerol (TAG) synthesis and subsequent accumulation of lipid droplets. Incorporation of fatty acid (FA) but not of glucose into TAG was enhanced by ELOVL2-overexpression. Two lipogenic genes encoding diacylglycerol acyltransferase-2 (DGAT2) and fatty acid-binding protein-4 (FABP4, aP2) were induced in ELOVL2-overexpressing cells, whereas no such effect was seen on the fatty acid synthase (FAS) gene.

Dietary methionine restriction (MR) produces an integrated series of biochemical and physiological responses that improve biomarkers of metabolic health, limit fat accretion, and enhance insulin sensitivity. The beneficial phenotype develops quickly after initiation of methionine restriction and persists after chronic consumption of the diet. The use of transcriptional profiling to guide tissue-specific evaluations of the molecular responses to MR has shown that liver and adipose tissue were the primary targets of a transcriptional program that effectively remodeled lipid metabolism in each tissue. In liver, the MR diet produced a coordinated down regulation of lipogenic genes and a corresponding reduction in the capacity of the liver to synthesize and export lipid. In contrast, the transcriptional response of white adipose tissue to dietary MR involved a depot-specific induction of lipogenic and oxidative genes and a commensurate increase in its capacity to both synthesize and oxidize fatty acids. The transcriptional and functional responses were accompanied by a significant change in adipocyte morphology, with the MR diet reducing cell size and increasing mitochondrial density across all depots. Insulin functions to compartmentalize lipid and carbohydrate metabolism in peripheral tissues and effect substrate switching during the transition between fed and fasted states. The coordinated transcriptional responses to dietary MR in liver and adipose tissue produced a reciprocal remodeling of lipid metabolism in the respective tissues and an overall reduction in circulating lipids. These results provide a mechanism for the increase in metabolic flexibility produced by the diet, and suggest that the targeted effects in these two tissues underlie the overall enhancement of insulin sensitivity.In the neurodegenerative disorder Niemann-Pick C (NPC) disease the intracellular trafficking of cholesterol is impaired resulting in cholesterol sequestration in late endosomes/lysosomes (LE/L). Recent studies have shown that cyclodextrin (CYCLO), a cholesterol sequestering agent, increases survival and improves neurodegeneration of Npc1 −/− mice. We have investigated (i) the cell types in the brain that respond to CYCLO, (ii) the CYCLO concentration that is beneficial, and (iii) mechanisms underlying the effects of CYCLO in neurons and glial cells from Npc1 −/− and Npc1 +/+ mice. Cells were incubated for 24 h with 0.1-10 mM CYCLO. 10 mM CYCLO killed all the neurons whereas neuron survival was not impaired by 0.1 mM or 1 mM CYCLO. Cholesterol sequestration in LE/L of Npc1 −/− cells was eliminated by 0.1 and 1 mM CYCLO. Moreover, 0.1 mM CYCLO reduced cholesterol synthesis and expression of genes involved in cholesterol synthesis and uptake, and markedly increased cholesterol esterification in Npc1 −/− astrocytes. In contrast, 1.0 mM CYCLO exerted the opposite effects on cholesterol homeostasis. Thus, cholesterol stored in LE/L of Npc1 −/− neurons, astrocytes and microglia is mobilized by low doses of CYCLO. The data support the hy...

Jörgensen JA, Zadravec D, Jacobsson A. Norepinephrine and rosiglitazone synergistically induce elovl3 expression in brown adipocytes.

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