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

Matsuda, Satoru; Kobayashi, Masaru; Kitagishi, Yasuko

doi:10.1155/2013/472432

Cited by 138 publications

(102 citation statements)

References 65 publications

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“…PTEN is among the proteins modified by TGFb1 and is a biological antagonist of PI 3 K signaling. Matsuda et al (2013) clarified the antagonistic relationship between PTEN and AKT and stated that PTEN has dual lipid and tyrosine-specific phosphatase activities that, if not physiologically regulated, could fundamentally alter cell behavior. Lan et al (2012) found that tubule PTEN was suppressed when TGFb1 signaling after AKI was persistently elevated and investigated its role in tubule repair.…”

Section: Discussionmentioning

confidence: 99%

Determinants of hepcidin levels in sepsis-associated acute kidney injury: Impact on pAKT/PTEN pathways?

Schaalan

Mohamed

2016

Journal of Immunotoxicology

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The antimicrobial b-defensin-like role of hepcidin (HEPC) has been increasingly investigated for its potential role in acute kidney injury (AKI). In sepsis-induced AKI, there is a complex interplay between positive and negative regulation of HEPC, with consequently altered distributions of iron caused by changes in HEPC levels. The aim of the current research was to assess serum HEPC levels in a cohort of septic patients with AKI and investigate the regulatory impact of hypoxia-inducing factor (HIF)-1a, erythropoietin (EPO) and inflammation on HEPC levels and related signal cascades in these patients. Baseline, higher levels of SCr (2.3-fold), blood urea nitrogen (BUN) (1.8-fold), uric acid (2.3-fold) and white blood cell (2.3-fold) were noted in septic AKI patients, along with decreased levels of albumin (15.7%), creatinine (44.7%) and BUN/ creatinine ratios (23.8%), compared to in normal subjects. These hosts also had increased serum levels of TNFa (4.4-times) and TGFb1 (3.2-times) compared to controls (p < 0.05). Further, HEPC and HIF-1a levels were also increased (8.8-and 3.6-times control levels), while EPO levels were decreased (77.8%) from control levels. After 12 weeks of antibiotic therapy, all septic AKI patients showed significant improvement of the altered markers of kidney dysfunction. In line with significant reductions in serum TNFa and TGFb1 (25.5% and 26.2%, respectively), HEPC and HIF-1a levels were significantly decreased (31.6% and 19.3%), and EPO levels increased (1.9-fold) compared to pretreatment values. There was a significant positive correlation between HEPC levels and kidney function markers (SCr and BUN), inflammatory TNFa and TGFb1 and serum HIF-1a and pAKT in septic AKI patients before and after treatment. Based on the results here, we conclude that HEPC, EPO and HIF-1a are involved in the pathogenesis of sepsis-induced AKI and confirm the dominating effects of inflammatory determinants over hypoxia-related complications.ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Determinants of hepcidin levels in sepsis-associated acute kidney injury: Impact on pAKT/PTEN pathways?

Schaalan

Mohamed

2016

Journal of Immunotoxicology

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“…This observation is consistent with a loss of activation of the AKT pathway, which has been identified as a key pathway for metabolism, cell growth, and cell survival. 36 Nevertheless, the PI3K/AKT pathways have been discussed to be the essential link between oxidative stress and inflammation in NASH. 36 Thus it is rather speculative if loss of AKT activation in AL mice on WD might be ascribed to the late phase of NAFLD with beginning carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

Kampschulte

Stöckl

Langheinrich

et al. 2014

Laboratory Investigation

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Nonalcoholic fatty liver disease has been linked to cardiovascular diseases and atherosclerosis. The aim of the current study was to characterize the hepatic pathology leading to fibrosis and tumors in a murine model of atherosclerosis.Male apolipoprotein E/low-density lipoprotein receptor double-knockout mice (AL) mice were fed with a high fat and high cholesterol western diet for 35 weeks (AL mice on WD). Protein and mRNA analysis as well as micro-computed tomography (micro-CT) were performed to assess oxidative stress, liver damage, inflammation, fibrosis, signaling pathways, vascularization, and tumorigenesis. Controls were chosen to distinguish between genetically and dietary effects in steatohepatitis and associated tumorigenesis. Hepatic inflammation and dyslipidemia were increased in AL mice on WD compared with wild-type mice on WD. Uniquely, AL mice on WD showed a spontaneous development of tumors (30% of cases) and thickening of intrahepatic vessel walls. Functionally relevant underlying signaling pathways such as NF-kB, Stat3, JNK, and AKT were differentially regulated between AL and wild-type mice on WD. Micro-CT was capable of visualizing and quantitatively distinguishing tumor neovascularization from vascularization in non-neoplastic liver tissue. AL mice on WD diet represent a novel model combining atherosclerosis and nonalcoholic fatty liver disease. Signaling pathways of liver cell damage and compensatory liver regeneration in combination with enhanced inflammation appear to be crucial for the spontaneous development of tumors in AL mice on WD. Micro-CT represents a new and powerful technique for the ultrastructural and three-dimensional assessment of the vascular architecture of liver tumors.

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“…The JAK2/STAT and the PI 3-kinase pathways regulate liver injury and regeneration [37], [38]. Thus, we hypothesized that hepatic SH2B1 may protect against liver injury as well as mediate growth hormone stimulation of somatic growth.…”

Section: Discussionmentioning

confidence: 99%

Hepatic SH2B1 and SH2B2 Regulate Liver Lipid Metabolism and VLDL Secretion in Mice

et al. 2013

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SH2B1 is an SH2 and PH domain-containing adaptor protein. Genetic deletion of SH2B1 results in obesity, type 2 diabetes, and fatty liver diseases in mice. Mutations in SH2B1 are linked to obesity in humans. SH2B1 in the brain controls energy balance and body weight at least in part by enhancing leptin sensitivity in the hypothalamus. SH2B1 in peripheral tissues also regulates glucose and lipid metabolism, presumably by enhancing insulin sensitivity in peripheral metabolically-active tissues. However, the function of SH2B1 in individual peripheral tissues is unknown. Here we generated and metabolically characterized hepatocyte-specific SH2B1 knockout (HKO) mice. Blood glucose and plasma insulin levels, glucose tolerance, and insulin tolerance were similar between HKO, albumin-Cre, and SH2B1f/f mice fed either a normal chow diet or a high fat diet (HFD). Adult-onset deletion of SH2B1 in the liver either alone or in combination with whole body SH2B2 knockout also did not exacerbate HFD-induced insulin resistance and glucose intolerance. Adult-onset, but not embryonic, deletion of SH2B1 in the liver attenuated HFD-induced hepatic steatosis. In agreement, adult-onset deletion of hepatic SH2B1 decreased the expression of diacylglycerol acyltransferase-2 (DGAT2) and increased the expression of adipose triglyceride lipase (ATGL). Furthermore, deletion of liver SH2B1 in SH2B2 null mice attenuated very low-density lipoprotein (VLDL) secretion. These data indicate that hepatic SH2B1 is not required for the maintenance of normal insulin sensitivity and glucose metabolism; however, it regulates liver triacylglycerol synthesis, lipolysis, and VLDL secretion.

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

Cited by 138 publications

References 65 publications

Determinants of hepcidin levels in sepsis-associated acute kidney injury: Impact on pAKT/PTEN pathways?

Determinants of hepcidin levels in sepsis-associated acute kidney injury: Impact on pAKT/PTEN pathways?

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

Hepatic SH2B1 and SH2B2 Regulate Liver Lipid Metabolism and VLDL Secretion in Mice

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