Hepatic p63 regulates steatosis via IKKβ/ER stress

Porteiro, Begoña; Fondevila, Marcos F.; Delgado, Teresa C.; Iglesias, Cristina; Imbernón, Mónica; Iruzubieta, Paula; Crespo, Javier; Zabala-Letona, Amaia; Fernø, Johan; González‐Terán, Bárbara; Matesanz, Nuria; Hernández‐Cosido, Lourdes; Marcos, Miguel; Tovar, Sulay; Vidal, Anxo; Sánchez-Ceinos, Julia; Malagón, Marı́a M.; Pombo, Celia M.; Zalvide, Juan; Carracedo, Arkaitz; Buqué, Xabier; Diéguez, Carlos; Sabio, Guadalupe; López, Miguel; Aspichueta, Patricia; Martínez‐Chantar, María Luz; Nogueiras, Rubén

doi:10.1038/ncomms15111

Cited by 46 publications

(91 citation statements)

References 63 publications

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“…A,E), indicating that ER stress has no effect on mGPDH. Moreover, TUDCA, a chemical chaperone that reduces ER stress, significantly blunted mGPDH deficiency–induced hepatic steatosis and lipid droplet accumulation and increased LW/BW and TG content and lipogenic gene PPARγ expression in vitro and in vivo (Fig. F‐K), suggesting mGPDH deletion accelerates TG accumulation and hepatic steatosis through activated ER stress.…”

Section: Resultsmentioning

confidence: 93%

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Zheng

Xiong

et al. 2019

Hepatology

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Mitochondrial glycerol 3‐phosphate dehydrogenase (mGPDH) is an integral component of the respiratory chain, and recent studies have suggested that it plays an important role in hepatic glucose homeostasis. However, its function in hepatic lipid metabolism is unclear. Here, we identified a role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from patients and mice with NAFLD (ob/ob, high‐fat diet [HFD] and db/db). Liver‐specific depletion of mGPDH in mice or mGPDH knockdown in cultured hepatocytes exacerbated diet‐induced triglyceride accumulation and steatosis through enhanced lipogenesis. RNA‐sequencing revealed that mGPDH regulated endoplasmic reticulum (ER)‐related proteins and processes. mGPDH deletion exacerbated tunicamycin (ER stress inducer)‐induced hepatic steatosis, whereas tauroursodeoxycholic acid (ER stress inhibitor) rescued mGPDH depletion–induced steatosis on an HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca2+ chelator 1,2‐bis (2‐aminophenoxy) ethane N,N,N´,N´‐tetraacetic acid acetoxymethyl ester, mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, or cyclophilin‐D (Cyp‐D) knockdown. mGPDH promoting Cyp‐D ubiquitination was also observed. Finally, liver‐specific mGPDH overexpression attenuated hepatic steatosis in ob/ob and HFD mice. Conclusion: mGPDH is a pivotal regulator of hepatic lipid metabolism. Its deficiency induces ER stress by suppressing Cyp‐D ubiquitination, a key regulator of the mitochondrial Ca2+ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.

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Section: Resultsmentioning

confidence: 93%

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Zheng

Xiong

et al. 2019

Hepatology

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“…The procedure for extraction of tissue TGs was based on methods described previously with some modifications. Livers (≈200 mg) were homogenized for 2 min in an ice‐cold chloroform–methanol mixture (2:1, vol/vol).…”

Section: Methodsmentioning

confidence: 99%

“…Besides their actions regulating the cell cycle and viability, tumor suppressors are emerging as important players in energy and glucose metabolism. For instance, some tumor suppressors such as p53 and PTEN are well known to affect adipocyte metabolism . The RB1 gene is the first tumor suppressor gene identified whose mutational inactivation is the cause of a human cancer.…”

Section: Introductionmentioning

confidence: 99%

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Cuñarro

Buqué

Casado

et al. 2018

Molecular Nutrition Food Res

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Scope The tumor suppressor p107, a pocket protein member of the retinoblastoma susceptibility protein family, plays an important role in the cell cycle and cellular adipocyte differentiation. Nonetheless, the mechanism by which it influences whole body Energy homeostasis is unknown. Methods and Results The phenotype of p107 knockout (KO) mixed‐background C57BL6/129 mice phenotype is studied by focusing on the involvement of white and brown adipose tissue (WAT and BAT) in energy metabolism. It is shown that p107 KO mice are leaner and have high‐fat diet resistence. This phenomenon is explained by an increase of energy expenditure. The higher energy expenditure is caused by the activation of thermogenesis and may be mediated by both BAT and the browning of WAT. Consequently, it leads to the resistance of p107 KO mice to high‐fat diet effects, prevention of liver steatosis, and improvement of the lipid profile and glucose homeostasis. Conclusion These data allowed the unmasking of a mechanism by which a KO of p107 prevents diet‐induced obesity by increasing energy expenditure via increased thermogenesis in BAT and browning of WAT, indicating the relevance of p107 as a modulator of metabolic activity of both brown and white adipocytes. Therefore, it can be targeted for the development of new therapies to ameliorate the metabolic syndrome.

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“…Moreover, obese NAFLD patients displayed increased expression of TAp63, IKKβ and XBP1s. This role of p63, a p53 ortholog, in lipid metabolism and NAFLD was not expected, although it was known to have a function in cellular adaptation to stress [128]. The IRE1-JNK pathway impaired hepatic insulin signaling transduction and triglyceride metabolism in a model of hepatic steatosis [129].…”

Section: Inflammationmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Metabolic Disorders

Ghemrawi

Battaglia-Hsu

Arnold

2018

Preprint

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Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these maladies has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic derangements stemmed from over nutrition frequently aggravated by modern sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults [1]. In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

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Hepatic p63 regulates steatosis via IKKβ/ER stress

Cited by 46 publications

References 63 publications

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

Endoplasmic Reticulum Stress in Metabolic Disorders

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