Livers with Constitutive mTORC1 Activity Resist Steatosis Independent of Feedback Suppression of Akt

Kenerson, Heidi L.; Subramanian, Savitha; McIntyre, Rebecca L.; Kazami, Machiko; Yeung, Raymond S.

doi:10.1371/journal.pone.0117000

Cited by 27 publications

(31 citation statements)

References 36 publications

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“…Insulin levels were not reduced in Insr/Tsc1 DLKO mice compared to Insr LKO / Tsc1 +/+ mice (Figure 6B). Liver triglyceride concentration was reduced in Insr +/+ / Tsc1 LKO as previously reported (Kenerson et al, 2015) and was also reduced in Insr/Tsc1 DLKO mice compared to Insr LKO / Tsc1 +/+ , indicating that the reduction in liver triglycerides was independent of insulin action (Figure 6C). To evaluate hepatic fat oxidation we examined fasting plasma ketone concentration.…”

Section: Resultssupporting

confidence: 87%

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity

et al. 2016

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Summary Dysregulated mitochondrial metabolism during hepatic insulin resistance may contribute to pathophysiologies ranging from elevated glucose production to hepatocellular oxidative stress and inflammation. Since obesity impairs insulin action but paradoxically activates mTORC1, we tested whether insulin action and mTORC1 contribute to altered in vivo hepatic mitochondrial metabolism. Loss of hepatic insulin action for 2-weeks caused increased gluconeogenesis, mitochondrial anaplerosis, TCA cycle oxidation and ketogenesis. However activation of mTORC1, induced by loss of hepatic Tsc1, suppressed these fluxes. Only glycogen synthesis was impaired by both loss of insulin receptor and mTORC1 activation. Mice with a double knockout of the insulin receptor and Tsc1 had larger livers, hyperglycemia, severely impaired glycogen storage and suppressed ketogenesis compared to loss of the liver insulin receptor alone. Thus, activation of hepatic mTORC1 opposes the catabolic effects of impaired insulin action under some nutritional states.

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Section: Resultssupporting

confidence: 87%

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity

et al. 2016

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“…In support of its catabolic role, hepatic targets of β‐catenin (acyl‐CoA dehydrogenases) were up‐regulated in PtenKO at 16 hours (http://onlinelibrary.wiley.com/doi/10.1002/hep.29226/suppinfo). However, chronic overactivity of the hypertrophic driver, mTORC1, may likewise promote β‐oxidation . We treated mice with moderate doses of the mTORC1 inhibitor rapamycin (1 mg/kg at 13 hours post‐PH and subsequently every 24 hours).…”

Section: Resultsmentioning

confidence: 99%

“…Recent findings indicate that mTORC1‐S6K can promote lipid oxidation in resting liver . However, rapamycin did not increase TG content in regenerating liver, suggesting either incomplete inhibition or promotion of TRAS catabolism by other PTEN‐regulated molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Given the steatotic phenotype of resting Pten –/– liver, TRAS might relate to PTEN down‐regulation after hepatectomy. Furthermore, recent evidence indicates also catabolic roles for AKT‐mTOR in hepatic lipid metabolism, perhaps implying that PTEN contributes to turnover of TRAS. Therefore, PTEN down‐regulation after hepatectomy might serve to orchestrate tissue growth with the resulting energy demands.…”

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confidence: 99%

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PTEN Down‐Regulation Promotes β‐Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice

Kachaylo¹,

Tschuor²,

Calo

et al. 2017

Hepatology

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PTEN down-regulation after hepatectomy promotes the burning of TRAS-derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands and emphasize the need of lipids for regeneration. (Hepatology 2017;66:908-921).

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“…Knockdown of hepatic S6 kinase 1 was correlated with reduced steatosis (13). In contrast, genetic manipulation to increase hepatic mTORC1 was not associated with hepatic fat accumulation, even in animals exposed to a high-fat diet (HFD) (14). The effect of mTOR signaling on hepatocellular protection in the setting of steatosis is currently unknown.…”

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confidence: 99%

mTOR activation protects liver from ischemia/reperfusion‐induced injury through NF‐κB pathway

Zhang

Mulholland

et al. 2017

FASEB j.

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Hepatic steatosis renders liver more vulnerable to ischemia/reperfusion injury (IRI), which commonly occurs in transplantation, trauma, and liver resection. The underlying mechanism is not fully characterized. We aimed to clarify the role of mechanistic target of rapamycin (mTOR) signaling in hepatic ischemia/reperfusion injury (HIRI) in normal and steatotic liver using - (AT) and (Am) transgenic mice. Steatotic liver induced by high-fat diet was more vulnerable to IRI. Activation of hepatic mTOR in AT mice decreased lipid accumulation attenuated HIRI as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, circulating levels of alanine aminotransferase and lactate dehydrogenase, and inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1), TNF-α, and IL-6 and hepatic cleaved caspase 3 in mice fed either a normal chow diet or a high-fat diet. The effects of mTOR activation on hepatic cleaved caspase 3 were reversed by rapamycin, an inhibitor of mTOR signaling. Inhibition of hepatic mTOR in Am mice increased hepatic lipid deposition and HIRI. The increment in hepatic susceptibility to IRI was significantly attenuated by pretreatment with IKKβ inhibitor. Further, suppression of mTOR facilitated nuclear translocation of NF-κB p65. In conclusion, our study suggests that mTOR activity in hepatocytes decreases hepatic vulnerability to injury through a mechanism dependent on NF-κB proinflammatory cytokine signaling pathway in both normal and steatotic liver.-Li, Z., Zhang, J., Mulholland, M., Zhang, W. mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-κB pathway.

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Livers with Constitutive mTORC1 Activity Resist Steatosis Independent of Feedback Suppression of Akt

Cited by 27 publications

References 36 publications

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity

PTEN Down‐Regulation Promotes β‐Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice

mTOR activation protects liver from ischemia/reperfusion‐induced injury through NF‐κB pathway

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