[Show abstract][Hide abstract] ABSTRACT: Depot-dependent differences in adipose tissue physiology may reflect specialized functions and local interactions between adipocytes and surrounding tissues. We combined time-resolved microarray analyses of mesenteric- (MWAT), subcutaneous- (SWAT) and epididymal adipose tissue (EWAT) during high-fat feeding of male transgenic ApoE3Leiden mice with histology, targeted lipidomics and biochemical analyses of metabolic pathways to identify differentially regulated processes and site-specific functions. EWAT was found to exhibit physiological zonation. De novo lipogenesis in fat proximal to epididymis was stably low, whereas de novo lipogenesis distal to epididymis and at other locations was down-regulated in response to high-fat diet. The contents of linoleic acid and α-linolenic acid in EWAT were increased compared to other depots. Expression of the androgen receptor (Ar) was higher in EWAT than in MWAT and SWAT. We suggest that Ar may mediate depot-dependent differences in de novo lipogenesis rate and propose that accumulation of linoleic acid and α-linolenic acid in EWAT is favored by testosterone-mediated inhibition of de novo lipogenesis and may promote further elongation and desaturation of these polyunsaturated fatty acids during spermatogenesis.
[Show abstract][Hide abstract] ABSTRACT: Background: In addition to its LDL-lowering effect, bile salt (BS) sequestration with Colesevelam HCl has recently been shown to improve glycaemic control in patients with type 2 diabetes. Interference with BS signaling through the nuclear receptor Fxr during resin therapy has been postulated to affect hepatic lipogenesis and plasma triglyceride levels. Yet, whether BS sequestration actually reduces BS pool size and alters BS signaling functions in vivo is not known. Methods: Lean C57Bl/6J and diabetic db/db mice were fed standard chow without or with Colesevelam HCl (2% w/w) for two weeks. Kinetic parameters of BS metabolism were assessed by stable isotope dilution using [2H4]cholate. Lipogenesis was determined from incorporation of [1-13C]-acetate (2% w/v in water) followed by MIDA analyses. Gene expression patterns were assessed by Q-PCR Results: Enhanced cholate synthesis (+375% and +172%, lean and db/db mice, respectively) fully compensated for its enhanced fractional turnover (3-fold in both strains) upon Colesevalam HCl-treatment in both groups: cholate pool size remained unaffected. Consequently, the transhepatic BS flux remained virtually unchanged and no indications for altered Fxr-activity were observed in either group. Yet, both lean (+50%) and db/db (+23%) mice showed significantly increased hepatic triglyceride contents upon resin feeding with a consistently increased hepatic expression of lipogenic genes (Srebp1c, Acc1, Fas, Scd1) and a clear induction of de novo lipogenesis. Complete absence of intestinal expression of Fgf15 in Colesevelam HCl-treated mice likely contributes to massively induced hepatic BS synthesis and might be involved in adaptations of hepatic lipid metabolism. Conclusion: Since BS pool size and transhepatic flux remained unaffected, induction of the hepatic lipogenic pathway of Colesevelam HCl-treated mice likely involves hepatic Fxr-independent mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Dyslipidemia is defined by abnormal levels of plasma lipoproteins. Several different types of dyslipidemia can be distinguished. An important group of drugs used in the treatment of dyslipidemia are the fibrates. Fibrates serve as agonists for the peroxisome proliferator-activated receptor alpha (PPAR¿), a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. By binding to response elements mostly present in the promoter of target genes, PPAR¿ governs the expression of numerous genes involved in a variety of metabolic processes. Activation of PPAR¿ results in a reduction of plasma TG levels, which is achieved by: (1) induction of genes that decrease the availability of TG for hepatic VLDL secretion, and (2) induction of genes that promote lipoprotein lipase-mediated lipolysis of TG-rich plasma lipoproteins. The stimulatory effect of PPAR¿ on plasma HDL levels in humans, which is opposite to what is observed in mice, appears to be mainly mediated via increased production of APOA1 and APOA2, the apolipoprotein constituents of HDL. Apart from its major actions outlined above, PPAR¿ modulates lipoprotein metabolism in several other ways, mostly via direct up-regulation of specific PPAR¿ target genes. By taking into account novel insights into the metabolism of plasma lipoproteins and by considering the latest information on PPAR¿-dependent gene regulation, a fresh perspective on the molecular mechanisms underlying the plasma lipoprotein modulating effect of PPAR¿ is presented.
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids : international journal of biochemistry, biophysics and molecular biology 1771 (2007) 8. 01/2007;
[Show abstract][Hide abstract] ABSTRACT: Recently, several proteins with homology to angiopoietins have been discovered. Three members of this new group, designated angiopoietin-like proteins (ANGPTLs), have been linked to regulation of energy metabolism. This review will focus on the fasting-induced adipose factor (FIAF)/ANGPTL4 as an important modulator of plasma lipid metabolism. FIAF/ANGPTL4 is a direct target of the insulin-sensitizing thiazolidinediones and hypolipidemic fibrate drugs. The collective data suggests that FIAF/ANGPTL4 plays an important role in the systemic partitioning of fatty acids, especially under fasting conditions. FIAF/ANGPTL4 prevents the clearance of plasma triglycerides and appears to stimulate adipose tissue lipolysis, resulting in lipids being redirected from storage to the circulation. FIAF/ANGPTL4 thus represents an interesting candidate for therapeutic targeting of dyslipidemia. It can be hypothesized that alterations in FIAF/ANGPTL4 signaling might be involved in dyslipidemia. While the importance of FIAF/ANGPTL4 in lipoprotein metabolism is well established, the effects of FIAF/ANGPTL4 on glucose homeostasis currently remain ambiguous
[Show abstract][Hide abstract] ABSTRACT: Glycerol, a product of adipose tissue lipolysis, is an important substrate for hepatic glucose synthesis. However, little is known about the regulation of hepatic glycerol metabolism. Here we show that several genes involved in the hepatic metabolism of glycerol, i.e., cytosolic and mitochondrial glycerol 3-phosphate dehydrogenase (GPDH), glycerol kinase, and glycerol transporters aquaporin 3 and 9, are upregulated by fasting in wild-type mice but not in mice lacking PPAR. Furthermore, expression of these genes was induced by the PPAR agonist Wy14643 in wild-type but not PPAR–null mice. In adipocytes, which express high levels of PPAR, expression of cytosolic GPDH was enhanced by PPAR and ß/ agonists, while expression was decreased in PPAR /– and PPARß/–/– mice. Transactivation, gel shift, and chromatin immunoprecipitation experiments demonstrated that cytosolic GPDH is a direct PPAR target gene. In line with a stimulating role of PPAR in hepatic glycerol utilization, administration of synthetic PPAR agonists in mice and humans decreased plasma glycerol. Finally, hepatic glucose production was decreased in PPAR-null mice simultaneously fasted and exposed to Wy14643, suggesting that the stimulatory effect of PPAR on gluconeogenic gene expression was translated at the functional level. Overall, these data indicate that PPAR directly governs glycerol metabolism in liver, whereas PPAR regulates glycerol metabolism in adipose tissue.
The Journal of Clinical Investigation 114 (2004) 1. 01/2004;
[Show abstract][Hide abstract] ABSTRACT: Background- Excessive exposure to dietary fats is an important factor in the initiation of obesity and metabolic syndrome associated pathologies. The cellular processes associated with the onset and progression of diet-induced metabolic syndrome are insufficiently understood. Principal Findings - To identify the mechanisms underlying the pathological changes associated with short and long-term exposure to excess dietary fat, hepatic gene expression of ApoE3Leiden mice fed chow and two types of high-fat (HF) diets was monitored using microarrays during a 16-week period. A functional characterization of 1663 HF-responsive genes reveals perturbations in lipid, cholesterol and oxidative metabolism, immune and inflammatory responses and stress-related pathways. The major changes in gene expression take place during the early (day 3) and late (week 12) phases of HF feeding. This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases. The most prominent switch occurs in the expression of inflammatory/immune pathways (early activation, late repression) and lipogenic/adipogenic pathways (early repression, late activation). Transcriptional network analysis identifies NF-¿B, NEMO, Akt, PPAR¿ and SREBP1 as the key controllers of these processes and suggests that direct regulatory interactions between these factors may govern the transition from early (stressed, inflammatory) to late (pathological, steatotic) hepatic adaptation to HF feeding. This transition observed by hepatic gene expression analysis is confirmed by expression of inflammatory proteins in plasma and the late increase in hepatic triglyceride content. In addition, the genes most predictive of fat accumulation in liver during 16-week high-fat feeding period are uncovered by regression analysis of hepatic gene expression and triglyceride levels. Conclusions - The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the reciprocal activation of NF-¿B and PPAR¿ regulators, emerges as the principal signature of the hepatic adaptation to excess dietary fat. These findings may be of essential interest for devising new strategies aiming to prevent the progression of high-fat diet induced pathologies
[Show abstract][Hide abstract] ABSTRACT: The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicle (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome