Reviews: current topicsrole of nuclear receptors in the regulation of gene expression by dietary fatty acids (review)

Khan, Seher A.; Heuvel, John P. Vanden

doi:10.1016/s0955-2863(03)00098-6

Cited by 134 publications

(104 citation statements)

References 124 publications

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“…Several genes are turned on by non-metabolized long-chain fatty acids in a physiologically relevant manner. 99,100 Therefore, it can be hypothesized that chronically elevated fatty acids, as observed in obese subjects, 78,101,102 may induce the expression of genes involved in the generation of leptin resistance. To date, no studies have investigated whether chronic exposure of skeletal muscle to high levels of fatty acids may affect the direct action of leptin in this tissue.…”

Section: Discussionmentioning

confidence: 99%

Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis

2005

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In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed.

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Section: Discussionmentioning

confidence: 99%

Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis

2005

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“…fatty acid synthase, acetyl-CoA carboxylase and stearoyl CoA desaturase) in adipose tissue and liver. They simultaneously induce the transcription of genes encoding proteins involved in lipid oxidation (carnitine palmitoyltransferase and acyl CoA oxydase), and fatty acid transport (L-FABP) in liver, in lipid transport proteins (FABP and aP2), fatty acid transporters (CD36, lipoprotein lipase) and adipokines (adiponectin and tumoral necrosis factor alpha (TNF-a) in white adipose tissue and in thermogenesis in brown adipose tissue [44][45][46] .…”

Section: Adipose Tissue Gene Expressionmentioning

confidence: 99%

The role of dietary fat in adipose tissue metabolism

Fernández‐Quintela

Churruca

Portillo

2007

Public Health Nutr.

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Energy intake and expenditure tend on average to remain adjusted to each other in order to maintain a stable body weight, which is only likely to be sustained if the fuel mix oxidised is equivalent to the nutrient content of the diet. Whereas protein and carbohydrate degradation and oxidation are closely adjusted to their intakes, fat balance regulation is less precise and that fat is more likely to be stored than oxidised.It has been demonstrated that dietary fatty acids have an influence not only on the fatty acid composition of membrane phospholipids, thus modulating several metabolic processes that take place in the adipocyte, but also on the composition and the quantity of different fatty acids in adipose tissue. Moreover, dietary fatty acids also modulate eicosanoid presence, which have hormone-like activities in lipid metabolism regulation in adipose tissue.Until recently, the adipocyte has been considered to be no more than a passive tissue for storage of excess energy. However, there is now compelling evidence that adipocytes have a role as endocrine secretory cells. Some of the adipokines produced by adipose tissue, such as leptin and adiponectin, act on adipose tissue in an autocrine/paracrine manner to regulate adipocyte metabolism. Furthermore, dietary fatty acids may influence the expression of adipokines.The nutrients are among the most influential of the environmental factors that determine the way adipose tissue genes are expressed by functioning as regulators of gene transcription. Therefore, not only dietary fat amount but also dietary fat composition influence adipose tissue metabolism. Keywords Dietary fatty acidsAdipose tissue Energy and macronutrient balancesAlthough quite variable from day to day, energy intake and energy expenditure tend to remain adjusted to each other on average in order to maintain a stable body weight. Such a steady state is likely to be sustained only if the fuel mix oxidised by the body is equivalent, in terms of its average composition, to the nutrient content of the diet consumed, so that protein balance, carbohydrate balance and fat balance are all achieved. As a result, long periods of weight stability imply not only that energy intake and energy expenditure are equivalent on average but also that the composition of the fuel mix oxidised is equal on average to the composition of the diet. Consequently, it can be stated that spontaneous adjustment of the rate of oxidation of a substrate to its rate of intake is obviously a major factor facilitating maintenance of substrate balance 1,2 . The rate of aminoacid oxidation and degradation is adjusted to protein intake, so that stable protein content is maintained. The rate of glucose disposal is also closely adjusted to carbohydrate intake because body glycogen reserves are small compared to glucose turnover, not being much larger than the amount of carbohydrate usually consumed and used in one day. Although the conversion of excess carbohydrate into fat can be proposed as a pathway for the disposal of carboh...

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“…The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exist as three subtypes (α, β/δ and γ), which exhibit tissue-specific expression, preferential ligand recognition, and distinct biological functions [4][5][6][7][8][9]. Although important as targets of pharmaceutical intervention, there is increasing evidence that the biological niche occupied by the PPARs is that of a receptor for fatty acid and their metabolites.…”

Section: Introductionmentioning

confidence: 99%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

104

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Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

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Reviews: current topicsrole of nuclear receptors in the regulation of gene expression by dietary fatty acids (review)

Cited by 134 publications

References 124 publications

Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis

Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis

The role of dietary fat in adipose tissue metabolism

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

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