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Mechanism of GDNF regulation of Hepatic Steatosis

Mechanism of GDNF regulation of Hepatic Steatosis
GDNF调控肝脂肪变性的机制
批准号:
9898210
负责人:
Shanthi K Srinivasan
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-04-01 至 2021-03-31

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Shanthi K Srinivasan的其他基金

相关文献

中文摘要
翻译
非酒精性脂肪性肝病(NAFLD)是退伍军人及其家属慢性肝病的常见病因
英文摘要
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in Veterans and its prevalence continues to increase, with the growing obesity epidemic. Hepatic steatosis is a component of NAFLD, wherein there is accumulation of triglycerides in the liver. Recently we published that GDNF transgenic mice fed a high fat diet are protected from obesity and the development of hepatic steatosis despite similar food intake and physical activity. GDNF transgenic mice over express GDNF in glia under the GFAP promoter (GDNF-tg) GDNF (expressed in glia) and its receptors, cRET and GFR-1 are expressed in human and murine hepatocytes. Thus, GDNF present in the liver can act locally on the hepatocytes. GDNF-tg mice demonstrate enhanced energy utilization assessed by indirect calorimetry. Having established a role for GDNF in preventing hepatic steatosis we recently examined the role of GDNF in preventing liver injury. Our preliminary data demonstrate novel effects of GDNF on the liver that include: (i) GDNF prevents HFD-induced liver injury (ii) GDNF-tg mice fed a HFD have increased hepatic levels of autophagy; and (iii) Hepatocytes treated with GDNF have improved mitochondrial function as seen by increased basal and mitochondrial respiration The mechanisms for these potentially beneficial effects of GDNF have yet to be explored. We hypothesize that the mechanism of GDNF prevention of hepatic injury is through promoting hepatocyte autophagy and by improving mitochondrial function leading to increased hepatocyte survival. GDNF can increase lipid droplet turnover, fat oxidation and oxidative phosphorylation in hepatic cells through the autophagic pathway. In this proposal we will establish the mechanism of GDNF regulation of hepatocyte autophagy and improved mitochondrial function. Currently there are no FDA approved drugs for the treatment of hepatic steatosis. We have identified a novel neurotrophic factor GDNF that decreases both hepatic steatosis and injury through enhancing autophagy and mitochondrial function. Using both genetic and pharmacological approaches we will define the role of GDNF in inducing autophagy to lead to oxidative lipid metabolism, fat reduction and reduced hepatic injury. We propose the following interrelated, but independently achievable aims: Specific Aim 1: To determine if the mechanism by which GDNF decreases hepatocyte lipid accumulation is through enhanced autophagy mediated lipolysis mediated by suppression of mTOR signaling. Preliminary data indicate that GDNF is a potent inducer of autophagy. We will establish whether autophagy mediates the GDNF-induced reduction in cellular lipid stores by studies of overexpression and knockdown of autophagy related genes. Preliminary data indicate that GDNF suppresses pmTOR signaling which is the prime inhibitory pathway of autophagy. We will determine the mechanism of GDNF up regulation of autophagy focusing on the mTOR pathway. WT and GDNF-tg mice will be fed a high fat diet for 8 weeks and genes regulating autophagy in hepatocytes will be assessed. In vitro the mechanism GDNF regulation of palmitate- induced autophagy will be determined focusing on the mTOR/TFEB/PGC1- pathway. Specific Aim 2: To establish that GDNF promotes hepatocyte survival by enhancing mitochondrial respiration by the mechanism of enhanced beta-adrenergic signaling and mitophagy. Our preliminary data demonstrate that GDNF increases mitochondrial function in hepatocytes as seen by increasing basal and maximal mitochondrial respiration as well as improving the mitochondrial respiration in hepatocytes cultured in the presence of palmitate. GDNF also promotes lipolysis through activation of -adrenergic signaling. We will establish the role of GDNF in regulating mitochondrial respiration using the GDNF-tg mice. We will examine the mechanism of GDNF regulation of mitochondrial health focusing on mitophagy and its effects on improving mitochondrial respiration. Taken together our data from this proposal may provide novel targets for the treatment or prevention of hepatic steatosis and injury.
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Role of GDNF in the regulation of pancreatic beta cell mass
  • 批准号:
    8195414
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2009
  • 负责人:
    Shanthi K Srinivasan
  • 依托单位:
Mechanism of Diabetic Enteric Neuropathy
  • 批准号:
    7730675
  • 项目类别:
  • 资助金额:
    $35.09万
  • 财政年份:
    2009
  • 负责人:
    Shanthi K Srinivasan
  • 依托单位:
Role of GDNF in the regulation of pancreatic beta cell mass
  • 批准号:
    7784485
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2009
  • 负责人:
    Shanthi K Srinivasan
  • 依托单位:
Role of GDNF in the regulation of hepatic steatosis
  • 批准号:
    8440394
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2009
  • 负责人:
    Shanthi K Srinivasan
  • 依托单位: