scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease

30 Jan 2013-International Scholarly Research Notices (Hindawi Publishing Corporation)-Vol. 2013, pp 472432-472432
TL;DR: Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis, and review recent studies on the features of the PTEN and the PI3K/AKT pathway.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome, which represents a range of fatty liver diseases associated with an increased risk of type 2 diabetes. Molecular mechanisms underlying how to make transition from simple fatty liver to nonalcoholic steatohepatitis (NASH) are not well understood. However, accumulating evidence indicates that deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in hepatocytes is a common molecular event associated with metabolic dysfunctions including obesity, metabolic syndrome, and the NAFLD. A tumor suppressor PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis. We review recent studies on the features of the PTEN and the PI3K/AKT pathway and discuss the protein functions in the signaling pathways involved in the NAFLD. The molecular mechanisms contributing to the diseases are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies for a condition.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
Jian Zhang1, Xiao-Hua Yu1, Yi-Guo Yan1, Cheng Wang1, Wen-Jun Wang1 
TL;DR: The aim of this review is to summarize the roles of the PI3K/Akt pathway in the development and progression of OS, and to highlight the therapeutic potential of targeting this signaling pathway.

233 citations

Journal ArticleDOI
TL;DR: Intacellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species generation, and the potential pathogenetic role of extracellular sources of reactive oxygen Species in NAFLD, including increased myeloperoxidase activity and oxidized low density lipoprotein accumulation, will be reviewed.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease in the world. It encompasses a histological spectrum, ranging from simple, nonprogressive steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. While liver-related complications are confined to NASH, emerging evidence suggests both simple steatosis and NASH predispose to type 2 diabetes and cardiovascular disease. The pathogenesis of NAFLD is currently unknown, but accumulating data suggest that oxidative stress and altered redox balance play a crucial role in the pathogenesis of steatosis, steatohepatitis, and fibrosis. We will examine intracellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species generation; additionally, the potential pathogenetic role of extracellular sources of reactive oxygen species in NAFLD, including increased myeloperoxidase activity and oxidized ...

131 citations

Journal ArticleDOI
TL;DR: Morin treatment attenuated the ACR-induced hepatorenal tissue injury by diminishing the serum AST, ALP, ALT, urea and creatinine levels and affected the protein levels by regulating the PI3K/Akt/mTOR signaling pathway and thus alleviated ACr-induced apoptosis and autophagy.

91 citations

Journal Article
TL;DR: In-depth study of the signal transductions will probably provide new suitable solutions for the prevention and therapy of NAFLD.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a common liver disease, and the incidence increases year by year. The pathogenesis of NAFLD is correlated with insulin resistant (IR), and oxidative stress which induces varied inflammatory cytokines (TNF-α, IL-1, IL-6, etc). Different signal transductions such as MAPK, NF-κB, AMPK, JAK2/STAT3, PPAR, PI3K/Akt, TLR were activated by the pathogenic factors to regulate correlative reactions. Thus, in-depth study of the signal transductions will probably provide new suitable solutions for the prevention and therapy of NAFLD.

78 citations

Journal ArticleDOI
TL;DR: It is found that paeoniflorin has therapeutic potential against NAFLD and that it acts through multiple signaling pathways, including regulating lipid metabolism and exerting insulin sensitizing effect by regulating the insulin signaling pathway IRS/Akt/GSK3β and anti-oxidation.
Abstract: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver diseases. This study sought to evaluate the insulin-sensitizing effect of paeoniflorin (PF) on high-fat diet-induced NAFLD and possible molecular mechanisms. Male Sprague Dawley rats were fed a high-fat diet (HFD) for 10 weeks to establish the NAFLD model, and PF (20 mg/kg/d) was gavaged to the NAFLD rats for another four weeks. Our results demonstrated that HFD resulted in hepatocellular ballooning, micro-/macrovesicular steatosis, and oxidative stress in the liver, accompanied by increased serum total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels and homeostasis model of insulin resistance (HOMA-IR) index. PF treatment improved the biochemical and histopathological changes in NAFLD rats. Moreover, we also found that PF could inhibit lipid ectopic deposition via regulating lipid metabolism (inhibiting lipid synthesis of cholesterol and de novo pathway), and exert insulin sensitizing effect by regulating the insulin signaling pathway IRS/Akt/GSK3β and anti-oxidation. The study findings suggest that PF has therapeutic potential against NAFLD and that it acts through multiple signaling pathways.

75 citations

References
More filters
Journal ArticleDOI
TL;DR: The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus, which will undoubtedly inform the rational design of novel therapies.
Abstract: Phosphatase and tensin homologue (PTEN) governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture Unravelling its enzymatic activities, its signalling partners, and the molecular mechanisms involved in the multiple levels of PTEN regulation will aid the design of novel PTEN-based therapeutic interventions in cancer The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer By suppressing the phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein–protein interactions, are all altered in cancer The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies

1,593 citations


"Roles for PI3K/AKT/PTEN Pathway in ..." refers background in this paper

  • ...PTEN is a dual-specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity [40, 41]....

    [...]

Book ChapterDOI
TL;DR: The purification of complexes participating in heterochromatin formation has allowed us to begin to analyse in detail the processes involved, and in the future this will help to understand how the RNAi machinery acts to induce the chromatin modifications which lead to heterochROMatin assembly in fission yeast.
Abstract: In the fission yeast Schizosaccharomyces pombe, the RNAi pathway plays an important role in the formation and maintenance of heterochromatin Heterochromatin, or silent chromatin, is an epigenetically inherited attribute of eukaryotic chromosomes which is required for gene regulation, chromosome segregation and maintenance of genome stability In S pombe, heterochromatin forms on related repetitive DNA sequences at specific loci These repetitive sequences, in concert with the RNAi machinery, are thought to attract several proteins including chromatin-modifying enzymes which act to promote heterochromatin formation The purification of complexes participating in heterochromatin formation has allowed us to begin to analyse in detail the processes involved In the future this will help us to understand how the RNAi machinery acts to induce the chromatin modifications which lead to heterochromatin assembly in fission yeast

1,173 citations

Journal ArticleDOI
TL;DR: Overall, this review outlines various mechanisms that lead to the development of oxidative stress and intervention and therapy that alter or disrupt these mechanisms may serve to reduce the risk of insulin resistance and theDevelopment of diabetes.

1,125 citations


"Roles for PI3K/AKT/PTEN Pathway in ..." refers background in this paper

  • ...Oxidative stress can be reduced by controlling hyperglycemia and calorie intake [24]....

    [...]

Journal ArticleDOI
TL;DR: The types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, should be monitored very carefully during clinical trial.

1,012 citations


Additional excerpts

  • ...HumanAKThas three isoforms: AKT1, AKT2, and AKT3 [34]....

    [...]

Journal ArticleDOI
TL;DR: It is argued that the conflict between hosts and viruses has led to the invention and diversification of molecular arsenals, which, in turn, promote the cellular co-option of endogenous viruses.
Abstract: Recent studies have uncovered myriad viral sequences that are integrated or 'endogenized' in the genomes of various eukaryotes. Surprisingly, it appears that not just retroviruses but almost all types of viruses can become endogenous. We review how these genomic 'fossils' offer fresh insights into the origin, evolutionary dynamics and structural evolution of viruses, which are giving rise to the burgeoning field of palaeovirology. We also examine the multitude of ways through which endogenous viruses have influenced, for better or worse, the biology of their hosts. We argue that the conflict between hosts and viruses has led to the invention and diversification of molecular arsenals, which, in turn, promote the cellular co-option of endogenous viruses.

741 citations