Key Genes Of Lipid Metabolism Research Articles

PPARδ Agonism Activates Fatty Acid Oxidation via PGC-1α but Does Not Increase Mitochondrial Gene Expression and Function

PPARδ (peroxisome proliferator-activated receptor δ) is a regulator of lipid metabolism and has been shown to induce fatty acid oxidation (FAO). PPARδ transgenic and knock-out mice indicate an involvement of PPARδ in regulating mitochondrial biogenesis and oxidative capacity; however, the precise mechanisms by which PPARδ regulates these pathways in skeletal muscle remain unclear. In this study, we determined the effect of selective PPARδ agonism with the synthetic ligand, GW501516, on FAO and mitochondrial gene expression in vitro and in vivo. Our results show that activation of PPARδ by GW501516 led to a robust increase in mRNA levels of key lipid metabolism genes. Mitochondrial gene expression and function were not induced under the same conditions. Additionally, the activation of Pdk4 transcription by PPARδ was coactivated by PGC-1α. PGC-1α, but not PGC-1β, was essential for full activation of Cpt-1b and Pdk4 gene expression via PPARδ agonism. Furthermore, the induction of FAO by PPARδ agonism was completely abolished in the absence of both PGC-1α and PGC-1β. Conversely, PGC-1α-driven FAO was independent of PPARδ. Neither GW501516 treatment nor knockdown of PPARδ affects PGC-1α-induced mitochondrial gene expression in primary myotubes. These results demonstrate that pharmacological activation of PPARδ induces FAO via PGC-1α. However, PPARδ agonism does not induce mitochondrial gene expression and function. PGC-1α-induced FAO and mitochondrial biogenesis appear to be independent of PPARδ.

Resistance Exercise Produces A Metabolic Gene Expression Signature Similar To Endurance Exercise

Resistance training (RT) has been proposed as a beneficial intervention modality for patients with metabolic syndrome and type II diabetes because of increasing evidence that similar metabolic benefits may be achieved with RT as with endurance training. Much of the improvements resulted from exercise training are associated with transient modifications in skeletal muscle induced by an acute bout of exercise. PURPOSE: to examine the transcriptional regulation of metabolic genes in skeletal muscle induced by an acute bout of resistance exercise (RE). METHODS: Subjects (11 female and 12 male, 18 to 40 y) trained the non-dominant elbow flexors for 12 weeks resulting in a 14.2 +/- 6.2 % increase in muscle volume and a 59.7 +/- 20.4% increase in 1RM strength. Six days after the last exercise session, an acute bout of RE was performed and bilateral biopsies were taken 4 hr post-exercise from both the trained and the untrained arms. RNA was extracted and prepared for expression profiling using the Affymetrix Human Genome U133 Plus 2 chips. Absolute expression values were calculated using MAS.5 and dChip and analysis was carried out using Gene Spring. RESULTS: RE induced augmented mRNA levels of regulators implicated in 1) mitochondrial biogenesis including PGC1-a (↑2.88, p=0.0015), SIRT1(↑1.25, p=0.0152) and PRKAG2 (↑4.80, p=0.0009); 2) insulin signaling including IRS2 (↑3.42, p=0.0010), RRAD (↑5.01, p=0.0007) and NR4A1 (↑4.48, p=0.0020); and 3) capillary biogenesis including VEGF (↑1.85, p=0.0027), HIF1A (↑1.67, p=0.0004) and CYR61 (↑3.02, p=0.0045). Transcriptional modification of key lipid metabolism genes favored fatty acid repartitioning towards esterification with mRNA levels for LPL and CPT1B being decreased (LPL, ↓1.71 fold, p=0.0001; CPT1B, ↓1.42 fold, p=0.0246), and for FABPs being increased (FABP4, ↑1.56 fold, p=0.0003; FABP5, ↑1.50, p=0.0065). CONCLUSION: Similar to endurance exercise, acute RE exhibits favorable regulation of metabolic gene transcription in skeletal muscle, implying, in part, an explanation for the beneficial role of resistance training in treating metabolic disturbances.

Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha: Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice

Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARα agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARα agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.

The physiology of long-distance migration: extending the limits of endurance metabolism

Long-distance migrants have evolved specific adaptations that make their athletic records possible. Unique mechanisms explaining their amazing capacity for endurance exercise have now been uncovered, particularly with respect to energy storage, mobilization, transport and utilization. Birds are champions of migration because flying offers a key compromise: it allows more rapid movement than swimming, but has a lower cost of transport than running. High efficiency for muscle contraction, pointed wings, low wingloading, travelling in V-formations, storing fuel as energy-dense lipids and atrophy of non-essential organs are some of their strategies to decrease the cost of transport. The ability to process lipids rapidly also emerges as a crucial component of the migrant phenotype. High lipid fluxes are made possible by lipoprotein shuttles and fatty acid binding proteins (FABPs) that accelerate lipid transport and by upgrading the metabolic machinery for lipolysis and lipid oxidation. Preparation for long flights can include natural doping on n-3 polyunsaturated fatty acids (n-3 PUFAs) from unique invertebrate diets. Muscle performance is improved by restructuring membrane phospholipids and by activating key genes of lipid metabolism through peroxisome proliferator-activated receptors (PPARs). The physiological secret to long migrations does not depend on a single ;magic' adaptation but on the integration of multiple adjustments in morphology, biomechanics, behavior, nutrition and metabolism. Research on the physiology of migrants improves the fundamental knowledge of exercise biology, but it also has important implications for wildlife conservation, treating obesity and improving the performance of human athletes.

Correlation between cell lipid content, gene expression and fermentative behaviour of two Saccharomyces cerevisiae wine strains

To verify a possible correlation between cell lipid composition, expression of key genes in lipid metabolism and fermentative behaviour of Saccharomyces cerevisiae wine strains. The fermentative abilities of two commercial wine strains of S. cerevisiae were tested under stressful conditions. Cell number, glucose and fructose concentrations, expression of ACS1, ACS2, ACC1, OLE1, ERG9, ERG10, ARE1 and ARE2 and lipid content were evaluated. The strain that failed to complete the fermentation had lower amounts of C16:1 and C16:0 fatty acids at the beginning of fermentation (0 h) and late logarithmic phase (72 h). While the amount of C18:1 in this strain was lower than that in the strain that completed the fermentation at 0 h, same levels were observed for both strains at 72 h. The sterol levels were generally higher in the strain that failed to complete the fermentation. Gene expression generally increased from the beginning of the fermentation to the late logarithmic phase in both strains. A positive correlation between good fermentative ability, elevated fatty acid content and ACC1 gene expression has been identified. The cell lipid content at the time of inoculum and expression of ACC1 gene of starter strains should be carefully considered in order to identify the possible stuck/sluggish fermentations.

Circulating lipids are lowered but pancreatic islet lipid metabolism and insulin secretion are unaltered in exercise-trained female rats

Deteriorating islet beta-cell function is key in the progression of an impaired glucose tolerance state to overt type 2 diabetes (T2D), a transition that can be delayed by exercise. We have previously shown that trained rats are protected from heart ischemia-reperfusion injury in correlation with an increase in cardiac tissue fatty-acid oxidation. This trained metabolic phenotype, if induced in the islet, could also prevent beta-cell failure in the pathogenesis of T2D. To assess the effect of training on islet lipid metabolism and insulin secretion, female Sprague-Dawley rats were exercised on a treadmill for 90 min/d, 4 d/week, for 10 weeks. Islet fatty-acid oxidation, the expression of key lipid metabolism genes, and glucose-stimulated insulin secretion were determined in freshly isolated islets from trained and sedentary control rats after a 48 h rest period from the last exercise. Although this moderate training reduced plasma glycerol, free fatty acids, and triglyceride levels by about 40%, consistent with reduced lipolysis from adipose tissue, it did not alter islet fatty-acid oxidation, nor the islet expression of key transcription factors and enzymes of lipid metabolism. The training also had no effect on glucose-stimulated insulin secretion or its amplification by free fatty acids. In summary, chronic exercise training did not cause an intrinsic change in islet lipid metabolism. Training did, however, substantially reduce the exposure of islets to exogenous lipid, thereby providing a potential mechanism by which exercise can prevent islet beta-cell failure leading to T2D.

Depot-Specific Modulation of Rat Intraabdominal Adipose Tissue Lipid Metabolism by Pharmacological Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.

Obesity-Related Glomerulopathy: Insights from Gene Expression Profiles of the Glomeruli Derived from Renal Biopsy Samples

Obesity-related glomerulopathy (ORG) is an important complication of obesity. The pathophysiological mechanism of glomerular injury in ORG is incompletely understood. Gene expression profiles in the glomeruli obtained from renal biopsy samples of patients with ORG were investigated, using a microdissection technique combined with Affymetrix microarray analysis. Six patients presented with obesity, proteinuria, and biopsy-proven ORG were enrolled. Two sex- and age-matched donor kidneys were applied as the controls. Glomeruli were dissected out from renal biopsy samples under microscope, and total RNA was extracted using RNeasy Micro kit. After two rounds of T7 promoter-based RNA amplification, gene expression profiles of the glomeruli samples were detected using Affymetrix U133A gene chips. Bioinformatic tools were applied to analyze the microarray data. Results of candidate ORG-related genes were further confirmed by real-time quantitative PCR and immunohistochemistry staining using renal biopsy samples of a larger pool of 15 ORG patients. Genes related to lipid metabolism, inflammatory cytokines, and insulin resistance were the most highlighted subgroups that significantly changed in the glomerular gene expression profiles of the ORG patients, compared with the controls. The expression levels of several key genes in lipid metabolism were increased over 2-fold, including low-density lipoprotein receptor, fatty acid binding protein 3, and sterol regulatory element binding protein 1. Moreover, some inflammatory cytokines and their downstream molecules were increased as well, including TNF-alpha and its receptors, IL-6 signal transducer, and interferon-gamma. As the indicators of insulin resistance in the local glomerular cells, levels of glucose-transporter 1, leptin receptor, peroxisome proliferator-activated receptor-gamma, and vascular endothelial growth factor increased, too. In addition to lipid dysmetabolism and insulin resistance, the activation of an inflammatory process in the glomeruli might play a unique role in the development of obesity-related glomerulopathy. Our results expand the understanding of obesity-induced glomerular injuries and shed light on new approaches in the treatment of this disease.

POLYUNSATURATED FATTY ACID REGULATION OF GENES OF LIPID METABOLISM

Apart from being an important macronutrient, dietary fat has recently gained much prominence for its role in regulating gene expression. Polyunsaturated fatty acids (PUFAs) affect gene expression through various mechanisms including, but not limited to, changes in membrane composition, intracellular calcium levels, and eicosanoid production. Furthermore, PUFAs and their various metabolites can act at the level of the nucleus, in conjunction with nuclear receptors and transcription factors, to affect the transcription of a variety of genes. Several of these transcription mediators have been identified and include the nuclear receptors peroxisome proliferator-activated receptor (PPAR), hepatocyte nuclear factor (HNF)-4alpha, and liver X receptor (LXR) and the transcription factors sterol-regulatory element binding protein (SREBP) and nuclear factor-kappaB (NFkappaB). Their interaction with PUFAs has been shown to be critical to the regulation of several key genes of lipid metabolism. Working out the mechanisms by which these interactions and consequent effects occur is proving to be complicated but is invaluable to our understanding of the role that dietary fat can play in disease management and prevention.

Sequence diversity in genes of lipid metabolism.

Elevated plasma lipoprotein levels play a crucial role in the development of coronary artery disease. Genetic factors strongly influence the levels of plasma lipoproteins, but the genes and sequence variations contributing to the most common forms of dyslipidemias are not known. We used GeneChip probe arrays to resequence the coding regions of 10 key genes of lipid metabolism. The sequences of these genes were analyzed in 80 dyslipidemic individuals. Fourteen nonsynonymous and twenty-two synonymous single nucleotide changes were identified that could be confirmed by conventional sequencing. Seven of the fourteen nonsynonymous sequence variants were polymorphisms with allele frequency >1% in the general population. The remaining seven were not found in normolipidemic controls (25 Caucasians and 25 African-Americans). The relationship between nonsynonymous sequence variations and various dyslipidemias was explored in association and family studies. No evidence was found for coding sequence variations in any of the 10 genes contributing to dyslipidemia. Only a single sequence variation, a missense mutation in the low density lipoprotein receptor gene, co-segregated with hyperlipidemia in the proband's family. This study illustrates some of the difficulties associated with identifying sequence variations contributing to complex traits.

A pathway model of lipid metabolism to predict the effect of genetic variability on lipid levels.

Complex phenotypes such as serum lipid concentrations involve numerous genes and require the analysis of the combined effects of these gene products. We modeled the interactions of six key lipid metabolism genes by means of differential equations. We tested the model by inserting the effects of known mutations in the low-density lipoprotein receptor gene and the lipoprotein lipase gene, as well as the effects of a high-fat diet, and observed that the predictions corresponded very well to published measurements. Models such as the one that we present here will become indispensable for analyzing and understanding the effects of variation in multiple genes.