Pyruvate Dehydrogenase Kinase 4

Cadoudal, Thomas; Distel, Emilie; Durant, Sylvie; Fouque, Françoise; Blouin, Jean-Marc; Collinet, Martine; Bortoli, Sylvie; Forest, Claude; Benelli, C

doi:10.2337/db08-0477

Cited by 98 publications

(88 citation statements)

References 40 publications

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“…This hypothesis indicates that Pdk4 and Dgat2 were upregulated in alcoholfed WT mice but not in Cd36 Ϫ / Ϫ mice. We speculate that increased Pdk4 expression would inhibit the pyruvate dehydrogenase complex with resultant effects on glyceroneogenesis ( 39,40 data also indicate that alcohol-fed Cd36 Ϫ / Ϫ mice had a reduced ability to synthesize TG because of a reduced enzymatic capacity to make TG, as well as reduced substrate availability for TG synthesis. Overall, these studies provide unique insight into the effects of alcohol and CD36 deficiency on hepatic lipid metabolism and the development of alcoholic steatosis, which appear to be independent of the potential role of CD36 in hepatic fatty acid uptake .…”

Section: Discussionmentioning

confidence: 91%

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

Clugston

Yuen

et al. 2014

Journal of Lipid Research

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liver failure ( 2 ). As a fi rst stage in the ALD spectrum, alcoholic steatosis has been extensively studied in humans and animal models to better understand the mechanisms leading to fat accumulation in the alcohol-exposed liver. This research has indicated that alcohol has many effects on hepatic lipid metabolism, including dysregulation of pathways associated with fatty acid (FA) synthesis, uptake, and oxidation, and triglyceride (TG) synthesis and export; however, the mechanisms underpinning these changes and their relative importance are only beginning to be understood ( 3 ).CD36 (also known as fatty acid translocase) is a class B scavenger receptor that is expressed on the cell surface and can recognize multiple ligands, including long-chain fatty acids, oxidized lipids, and lipoproteins ( 4 ). CD36 has multiple cell type-specifi c physiological functions; for example, its expression in microvascular endothelial cells is associated with angiogenesis, and in the apical cells of taste buds, it is associated with the detection of dietary fatty acids ( 4, 5 ). CD36 is also a mediator of free fatty acid (FFA) uptake into tissues, particularly adipose, heart, and skeletal muscle ( 6, 7 ). It is thought that CD36 does not normally play a signifi cant role in hepatic FFA uptake; however, under nonphysiological conditions, CD36 is induced in the liver and may contribute to hepatic steatosis ( 6 ). For example, pharmacologic activation of liver X receptors increases CD36 expression and TG accumulation in the liver ( 8 ), adenoviral-mediated overexpression of hepatic CD36 increases FFA uptake and TG accumulation ( 9 ), and liver tissues obtained from patients with nonalcoholic fatty liver disease also have significantly elevated CD36 expression ( 10 ).Our group and others have observed increased hepatic CD36 expression in alcohol-fed mice at the gene and protein levels ( 11-13 ). Given the role of CD36 in facilitating FFA uptake into tissues and the observation that it is upregulated in the alcohol-exposed liver, we hypothesized that CD36 is Abstract CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFAs). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFAs, which then serve as a substrate for triglyceride (TG) synthesis and the development of alcoholic steatosis. We investigated this hypothesis in alcohol-fed wild-type and Cd36 -defi cient ( Cd36 ؊ / ؊ ) mice using low-fat/high-carbohydrate Lieber-DeCarli liquid diets, positing that Cd36 ؊ / ؊ mice would be resistant to alcoholic steatosis. Our data show that the livers of Cd36 ؊ / ؊ mice are resistant to the lipogenic effect of consuming highcarbohydrate liquid diets. These mice also do not further develop alcoholic steatosis when chronically fed alcohol. Surprisingly, we did not detect an effect of alcohol or CD36 deficiency on hepatic FFA uptake; however, the lower baseline levels of hepatic TG in ...

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Section: Discussionmentioning

confidence: 91%

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

Clugston

Yuen

et al. 2014

Journal of Lipid Research

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“…In contrast to RGZ, amorfrutin B further showed reduced RNA expression of the cortisol generating hydroxysteroid (11-β) dehydrogenase 1 (HSD11B1), which is linked to central obesity [12]. Additionally, amorfrutin B treatment led to decreased transcription of pyruvate dehydrogenase kinase 4 (PDK4), encoding a glycerogenesis-activating enzyme linked to excess lipid storage in adipocytes [13]. However, amorfrutin B treatment also resulted in increased phosphodiesterase 3B (PDE3B) expression, which is responsible for beneficial NEFA release in TZD-treated mice [14].…”

Section: Resultsmentioning

confidence: 99%

Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent glucose-lowering properties

et al. 2013

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Aims/hypothesis The nuclear receptor peroxisome proliferatoractivated receptor gamma (PPARγ) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARγ-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose-lowering compound that selectively modulates PPARγ. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARγ-binding and pharmacological properties of this family of plant metabolites. Methods Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg −1 day −1 amorfrutin B. Results Amorfrutin B showed low nanomolar binding affinity to PPARγ, and micromolar binding to the isotypes PPARα and PPARβ/δ. Amorfrutin B selectively modulated PPARγ activity at low nanomolar concentrations. In insulinresistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention. Conclusions/interpretation The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes.

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“…In fact, fasting caused a significant increase in lipolysis but did not influence the absolute amount of FFA re-esterification (Wang et al, 2003). Recent findings suggest that upregulation of PDK4 expression plays an important role in supplying glycerol-3-phosphate for the re-esterification into TG of FFA arising from lipolysis in WAT during fasting in rats (Cadoudal et al, 2008). There is evidence that PDK4 activity is regulated not only by gene expression but also by allosteric effectors (Jeong et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Fasting and Glucagon Stimulate Gene Expression of Pyruvate Dehydrogenase Kinase 4 in Chickens

et al. 2017

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The excessive accumulation of body fat has become a serious problem in the broiler industry. However, the molecular mechanisms underlying the regulation of lipid metabolism-related genes in broiler chickens are not fully understood. In the present study, we investigated the role of glucagon on the expression of lipid metabolism-related genes in chicken white adipose tissue (WAT). Four hours of fasting significantly increased plasma levels of free fatty acid in broiler chickens. The mRNA levels of adipose triglyceride lipase (ATGL) and pyruvate dehydrogenase kinase 4 (PDK4) in abdominal WAT significantly increased by fasting, whereas the mRNA levels of diacylglycerol O-acyltransferase homolog 2 (DGAT2) and peroxisome proliferator-activated receptor-γ (PPARγ) significantly decreased. The results suggest that fasting stimulates lipolysis and suppresses adipogenesis and re-esterification of TG in chicken WAT. Glucagon significantly increased the mRNA levels of PDK4 in chicken primary adipocytes, whereas there were no significant changes in the mRNA levels of ATGL, DGAT2, and PPARγ. Our findings suggest that glucagon upregulates PDK4 expression and may stimulate lipolysis without affecting the expression of ATGL in chicken WAT.

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Pyruvate Dehydrogenase Kinase 4

Cited by 98 publications

References 40 publications

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent glucose-lowering properties

Fasting and Glucagon Stimulate Gene Expression of Pyruvate Dehydrogenase Kinase 4 in Chickens

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