HIF2 α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling

Ramakrishnan, S; Zhang, Huabing; Takahashi, Shogo; Centofanti, Brook; Periyasamy, Sarvesh; Weisz, K; Chen, Zheng; Uhler, Michael D.; Rui, Liangyou; Gonzalez, Frank J.; Shah, Yatrik M.

doi:10.1016/j.cmet.2016.01.004

Cited by 47 publications

(53 citation statements)

References 45 publications

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“…4d ). As ENTPD5 is also shown to activate the phosphoinositide-3 kinase/Akt pathway 36 , we the asked whether HRD1-mediated ENTPD5 protein destruction affects glucose metabolism through the insulin-Akt signaling pathway. Consistent with this hypothesis, we observed that the phosphorylation, but not total protein expression levels, of Akt, as well as its downstream targets Foxo1 and S6K, were significantly elevated in HRD1 Alb liver compared to control liver tissue, indicating that HRD1 deletion enhances the activation of the insulin signaling pathway in liver (Fig.…”

Section: Resultsmentioning

confidence: 99%

ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes

Wei

Yuan

et al. 2018

Nat Commun

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The HMG-CoA reductase degradation protein 1 (HRD1) has been identified as a key enzyme for endoplasmic reticulum-associated degradation of misfolded proteins, but its organ-specific physiological functions remain largely undefined. Here we show that mice with HRD1 deletion specifically in the liver display increased energy expenditure and are resistant to HFD-induced obesity and liver steatosis and insulin resistance. Proteomic analysis identifies a HRD1 interactome, a large portion of which includes metabolic regulators. Loss of HRD1 results in elevated ENTPD5, CPT2, RMND1, and HSD17B4 protein levels and a consequent hyperactivation of both AMPK and AKT pathways. Genome-wide mRNA sequencing revealed that HRD1-deficiency reprograms liver metabolic gene expression profiles, including suppressing genes involved in glycogenesis and lipogenesis and upregulating genes involved in glycolysis and fatty acid oxidation. We propose HRD1 as a liver metabolic regulator and a potential drug target for obesity, fatty liver disease, and insulin resistance associated with the metabolic syndrome.

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Section: Resultsmentioning

confidence: 99%

ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes

Wei

Yuan

et al. 2018

Nat Commun

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“…Tissue iron detection was performed in formalin-fixed, paraffin-embedded sections stained with Prussian blue. For immunohistochemical analysis, frozen sections were probed with polyclonal rabbit anti-HIF-2α antibody (100-122, Novus), as previously described (47).…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis. Whole-cell, nuclear, and membrane lysates were prepared as described previously (10,47). In brief, lysates were separated by SDS-PAGE, transferred onto nitrocellulose membranes, and probed overnight at 4°C with antibodies against FPN (MTP11-A, Alpha Diagnostic International [ADI]), DMT1 (NRAMP21-A, ADI), DCYTB (DCYTB-11A, ADI), and TFR1 (13-6800, Invitrogen, Thermo Fisher Scientific) for mouse tissue lysates; FPN (NBP1-21502, Novus), FTH1 (3998S, Cell Signaling Technology), GAPDH (sc-47724, Santa Cruz Biotechnology), GFP (sc-996, Santa Cruz Biotechnology), lamin…”

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confidence: 99%

Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload

Schwartz

Das

Ramakrishnan

et al. 2018

Journal of Clinical Investigation

160

122

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“…AlbuminCre transgenic mice have been used extensively for liverspecific targeting of genes (27,28). Smad3 flox/flox:albCreϩ and T␤RI flox/flox:albCreϩ mice showed a marked improvement in PTT and glucagon tolerance tests (Fig.…”

Section: Tgf-␤1/smad3 Signaling Is Associated With Physiologicallymentioning

confidence: 99%

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

Yadav

Devalaraja

Chung

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinMaintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-␤1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-␤1/Smad3 signals suppressed endogenous glucose production. TGF-␤1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-␤1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-␤1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.Glucose homeostasis is achieved via the integration of physiological processes occurring in multiple organs. Glycolysis and gluconeogenesis represent two competing processes that regulate blood glucose levels (1). Hepatic gluconeogenesis is a critical mechanism for endogenous glucose production during periods of prolonged fasting. However, deregulated hepatic gluconeogenesis is a common feature in patients with type 2 diabetes (T2D) 2 (2). Expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatases (G6Pase) (3), key rate-limiting enzymes for hepatic gluconeogenesis, increases abnormally in T2D (4). Likewise, the transgenic overexpression of these enzymes in mice results in hyperglycemia, hyperinsulinemia, and insulin resistance (5, 6). In contrast, deletion of PEPCK reverses hyperglycemia and insulin resistance in diabetes-prone db/db mice (7).The AMP-activated protein kinase (AMPK) signaling pathway, among others, regulates the expression of PEPCK and G6Pase (8). AMPK is a heterotrimeric protein, consisting of ␣1/2, ␤1/2, and ␥1/2/3 subunits, that regulates glucose and fatty acid metabolism (9). Phosphorylation of Thr-172 in the ␣1 subunit is important for AMPK activation, which is in turn regulated by two upstream kinases, LKB1 and Ca 2ϩ calmodulin-dependent protein kinases ␣ ...

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HIF2 α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling

Cited by 47 publications

References 45 publications

ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes

ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes

Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

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