Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN

Piguet, Anne‐Christine; Stroka, Deborah; Zimmermann, Arthur; Dufour, Jean‐François

doi:10.1042/cs20090313

Cited by 77 publications

(70 citation statements)

References 45 publications

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“…[44][45][46] CYP2E1 activity has been correlated with hypoxemia in the liver, chronic pulmonary disease, and heart failure in vivo and in vitro. [47][48][49][50] Thus, it is possible that hypoxemia in a state of cardiomyopathy triggers the formation of acetone, which then induces CYP2E1 to enhance the metabolism of endogenous ketones to meet the energy demand of the heart. The expression of CYP2E1 increases significantly in heart diseases, [13][14][15][16][17] and here we found that the expression of CYP2E1 also increased in ADR-induced DCM heart and Lmna E82K DCM mice ( Figure 1A and 1B).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Zhang

et al. 2012

Hypertension

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Abstract-Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT R141W and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of ␣-myosin heavy chain (MHC)-cTnT R141W ϫCYP2E1-silence double-transgenic mice when compared with the cTnT R141W transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome c, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT R141W transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT R141W or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.

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Section: Discussionmentioning

confidence: 99%

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Zhang

et al. 2012

Hypertension

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“…These activities could be attributed (at least partially) to several mechanisms as follows: (i) the inhibition of the endogenous Fasn up-regulation, a hypoxia-induced Pparg target (39); (ii) an interference with fatty acid synthesis by preventing Acaca upregulation, which is also a Pparg-regulated gene induced by hypoxia (38); and (iii) the enhancement of the fatty acid metabolism by re-sensitization of Adipor1 and Prkaa-mediated signaling (14). As a consequence, GRK2 inhibition retarded the development of the dysfunctional cardiac substrate use characteristic of late-stage heart failure (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, GRKInh largely prevented the up-regulation of Acaca, i.e. a gene up-regulated by hypoxia (38), which was commonly triggered at the onset of heart failure induced by Tg-FASN, pressure overload, and Pparg (Fig. 7C and cf.…”

Section: Grk2 Inhibition By Grkinh Prevents the Dysfunctional Cardiacmentioning

confidence: 99%

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Alla

Graemer

et al. 2016

Journal of Biological Chemistry

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Impairment of myocardial fatty acid substrate metabolism is characteristic of late-stage heart failure and has limited treatment options. Here, we investigated whether inhibition of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolism of late-stage heart failure. The heart failure-like substrate metabolism was reproduced in a novel transgenic model of myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. The increased fatty acid utilization of FASN transgenic neonatal cardiomyocytes rapidly switched to a heart failure phenotype in an adult-like lipogenic milieu. Similarly, adult FASN transgenic mice developed signs of heart failure. The development of disturbed substrate utilization of FASN transgenic cardiomyocytes and signs of heart failure were retarded by the transgenic expression of GRKInh, a peptide inhibitor of GRK2. Cardioprotective GRK2 inhibition required an intact ERK axis, which blunted the induction of cardiotoxic transcripts, in part by enhanced serine 273 phosphorylation of Pparg (peroxisome proliferator-activated receptor ␥). Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes. Thus, GRK2 inhibition is a novel approach that targets the dysfunctional substrate metabolism of the failing heart.Heart failure is a debilitating syndrome that involves insufficient cardiac performance. Multiple pathomechanisms have been elucidated, but treatment options remain insufficient, and hence the mortality of heart failure is high (1). The causes of heart failure are complex with ischemic heart disease being the most frequently associated condition (2). Co-existing disorders such as diabetes, hypertension, and obesity further deteriorate symptoms (3). Despite having a different etiology, late-stage heart failure is commonly characterized by severe changes in myocardial substrate metabolism, with a switch from fatty acid oxidation toward predominant glycolysis (4 -6). Conflicting evidence exists as to whether this substrate switch is beneficial or detrimental (7), but several previous studies have indicated that an increased availability of lipid substrates that counteract the substrate switch could improve cardiac function (7,8). Moreover, treatment options, which improve substrate availability, are attractive because the failing heart is often considered to be "an engine running out of fuel" (9).Following this concept, we aimed to investigate the impact of improved cardiac substrate availability by generating transgenic mice with myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. Such an approach is also supported by data obtained for myocardium-specific Fasn deficiency, which have revealed the cardioprotective potential of Fasn (10). Moreover, hearts from patients with heart failure showed an increased express...

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“…flow, 11,12 gut-derived endotoxin and ethanol, 13,14 and dysregulation of adipokine 15,16 and cytokine production. 17,18 While the exact etiology of NAFLD and NASH is unclear, insulin resistance appears to be central to the pathogenesis of NASH by allowing inappropriate levels of lipolysis from the adipose tissue and impairing peripheral glucose disposal.…”

Section: Journal Of Clinical and Experimental Hepatologymentioning

confidence: 99%

Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis

Le¹,

Loomba²

2012

Journal of Clinical and Experimental Hepatology

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations. (J CLIN EXP HEPATOL 2012;2:156-173)

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Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN

Cited by 77 publications

References 45 publications

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis

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Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN

Cited by 77 publications

References 45 publications

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis

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Product

Resources

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Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice