Fasting-Induced Hepatic Production of DHEA is Regulated by PGC-1α, ERRα and HNF4α

Grasfeder, Linda L.; Gaillard, Stéphanie; Hammes, Stephen R.; Newgard, Christopher B.; Hochberg, Richard B.; Dwyer, Mary A.; Chang, Ching‐yi; McDonnell, Donald P.

doi:10.1210/jcem.94.6.9994

Cited by 4 publications

(5 citation statements)

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“…PGC-1␣ is a transcriptional coactivator of PPAR-␥ and other nuclear hormones (13,30,42). Repression of PGC-1␣ caused abnormal mitochondrial morphology and downregulation of mitochondria-related enzymes (6).…”

Section: Adr Induced Podocyte Injury and Mitochondrial Dysfunctionmentioning

confidence: 99%

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

Zhu

Xuan

Che

et al. 2014

American Journal of Physiology-Renal Physiology

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Adriamycin (ADR)-induced nephropathy in animals is an experimental analog of human focal segmental glomerulosclerosis, which presents as severe podocyte injury and massive proteinuria and has a poorly understood mechanism. The present study was designed to test the hypothesis that the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α-mitochondria axis is involved in ADR-induced podocyte injury. Using MPC5 immortalized mouse podocytes, ADR dose dependently induced downregulation of nephrin and podocin, cell apoptosis, and mitochondrial dysfunction based on the increase in mitochondrial ROS production, decrease in mitochondrial DNA copy number, and reduction of mitochondrial membrane potential and ATP content. Moreover, ADR treatment also remarkably reduced the expression of PGC-1α, an important regulator of mitochondrial biogenesis and function, in podocytes. Strikingly, PGC-1α overexpression markedly attenuated mitochondrial dysfunction, the reduction of nephrin and podocin, and the apoptotic response in podocytes after ADR treatment. Moreover, downregulation of PGC-1α and mitochondria disruption in podocytes were also observed in rat kidneys with ADR administration, suggesting that the PGC-1α-mitochondria axis is relevant to in vivo ADR-induced podocyte damage. Taken together, these novel findings suggest that dysfunction of the PGC-1α-mitochondria axis is highly involved in ADR-induced podocyte injury. Targeting PGC-1α may be a novel strategy for the treatment of ADR nephropathy and human focal segmental glomerulosclerosis.

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Section: Adr Induced Podocyte Injury and Mitochondrial Dysfunctionmentioning

confidence: 99%

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

Zhu

Xuan

Che

et al. 2014

American Journal of Physiology-Renal Physiology

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“…Taken together, these data indicate a possible implication of the eNOS/PGC1a/CREB pathway in the effects of DHEA. Interestingly, a recent study [37] indicates that PGC1a controls DHEA synthesis in the liver. Together with our observations, this could indicate that DHEA participates in feedback control of PGC1a expression or activation.…”

Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone reverses chronic hypoxia/reoxygenation-induced right ventricular dysfunction in rats

et al. 2012

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Dehydroepiandrosterone (DHEA) prevents chronic hypoxia-induced pulmonary hypertension and associated right ventricle dysfunction in rats. In this animal model, reoxygenation following hypoxia reverses pulmonary hypertension but not right ventricle dysfunction. We thus studied the effect of DHEA on the right ventricle after reoxygenation, i.e. after a normoxic recovery phase secondary to chronic hypoxia in rats.Right ventricle function was assessed in vivo by Doppler echocardiography and in vitro by the isolated perfused heart technique in three groups of animals: control, recovery (21 days of hypoxia followed by 21 days of normoxia) and recovery DHEA (30 mg?kg -1 every 2 days during the recovery phase). Right ventricle tissue was assessed by optical and electron microscopy. DHEA abolished right ventricle diastolic dysfunction, as the echographic E wave remained close to that of controls (mean¡SD 76.5¡2.4 and 79.7¡1.7 cm?s -1 , respectively), whereas it was diminished to 40.3¡3.7 in the recovery group. DHEA also abolished right ventricle systolic dysfunction, as shown by the inhibition of the increase in the slope of the pressure-volume curve in isolated heart. The DHEA effect was related to cardiac myocytes proliferation.In conclusion, DHEA prevents right ventricle dysfunction in this animal model by preventing cardiomyocyte alteration. KEYWORDS: Cardiac myocyte, chronic hypoxia, dehydroepiandrosterone, mitochondria, pulmonary hypertension T ypical chronic lung hypoxaemic diseases, such as chronic obstructive pulmonary disease (COPD) [1], can lead to pulmonary hypertension (PH) and ultimately to right ventricular failure [2][3][4]. Rodents exposed to chronic hypoxia, either normo-or hyperbaric, consistute a classical animal model used to investigate mechanisms as well as therapeutic targets in this pulmonary vascular disease [5,6]. In a rat model of hypobaric chronic hypoxia, we have previously demonstrated that dehydroepiandrosterone (DHEA), an adrenal steroid, prevents and decreases hypoxic PH and associated right ventricle hypertrophy [7]. In the same animal model, reoxygenation following hypoxia, i.e. a normoxic recovery phase of 21 days of normoxia secondary to a chronic hypoxic period of 21 days, also reverses PH as it normalises pulmonary pressure and antagonises vascular remodelling [8]. However, such normoxic recovery period does not correct right ventricular dysfunction [9].We believe that such an experimental model may be relevant in patients suffering from COPD, as they may alternate between successive severe hypoxic episodes related to exacerbations [10] and fewer hypoxic episodes related their oxygen therapy [11].As mentioned, DHEA has been studied in animal [7,12] and human PH [13,14]. More recently, it has been shown that DHEA can modulate cardiac function. DHEA reverses left ventricular stiffness and fibrosis, which typically accompanies ageing in mice [15], and decreases the production of type I collagen by cardiac fibroblasts [16]. DHEA can also modulate oxidative stress in the rat h...

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“…Indeed, PGC-1α was reported to trigger the female hormones synthesis in breast adipose tissue and ovarian granulosa cells (35,36). While it was also reported that fasting-induced PGC-1α upregulation mediated the hepatic synthesis of female hormone precursors without significant changes in these hormones themselves in vitro (32). C/EBPβ activates PGC-1α during liver proliferation with an amplitude of induction that exceeds the fasting response (28), which may lead to the regulation of PGC-1α to these female hormones during liver proliferation.…”

Section: Firstmentioning

confidence: 99%

“…C6 again suggested that the decreased serum TC was closely related to the complement system. Pgc1α is involved in regulating steroid hormone biosynthesis (31)(32)(33). Thus, the complement system and PGC-1α may be effectors in the SAK-HV-induced cholesterol metabolism disturbance.…”

Section: Stat3-c/ebpβ-pgc-1α Was Screened Out By Weighted Gene Co-expmentioning

confidence: 99%

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

Zhang¹,

Huang²,

Jing³

et al. 2017

Theranostics

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The accumulations of excess lipids within liver and serum are defined as non-alcoholic fatty liver disease (NAFLD) and hyperlipemia respectively. Both of them are components of metabolic syndrome that greatly threaten human health. Here, a recombinant fusion protein (SAK-HV) effectively treated NAFLD and hyperlipemia in high-fat-fed ApoE -/- mice, quails and rats within just 14 days. Its triglyceride and cholesterol-lowering effects were significantly better than that of atorvastatin during the observation period. We explored the lipid-lowering mechanism of SAK-HV by the hepatic transcriptome analysis and serials of experiments both in vivo and in vitro . Unexpectedly, SAK-HV triggered a moderate energy and material-consuming liver proliferation to dramatically decrease the lipids from both serum and liver. We provided the first evidence that PGC-1α mediated the hepatic synthesis of female hormones during liver proliferation, and proposed the complement system-induced PGC-1α-estrogen axis via the novel STAT3-C/EBPβ-PGC-1α pathway in liver as a new energy model for liver proliferation. In this model, PGC-1α ignited and fueled hepatocyte activation as an “igniter”; PGC-1α-induced estrogen augmented the energy supply of PGC-1α as an “ignition amplifier”, then triggered the hepatocyte state transition from activation to proliferation as a “starter”, causing triglyceride and cholesterol-lowering effects via PPARα-mediated fatty acid oxidation and LDLr-mediated cholesterol uptake, respectively. Collectively, the SAK-HV-triggered distinctive lipid-lowering strategy based on the new energy model of liver proliferation has potential as a novel short-period biotherapy against NAFLD and hyperlipemia.

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Fasting-Induced Hepatic Production of DHEA is Regulated by PGC-1α, ERRα and HNF4α

Cited by 4 publications

References 0 publications

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

Dehydroepiandrosterone reverses chronic hypoxia/reoxygenation-induced right ventricular dysfunction in rats

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

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