Pioglitazone Reduces ER Stress in the Liver: Direct Monitoring of in vivo ER Stress Using ER Stress-activated Indicator Transgenic Mice

Yoshiuchi, Kazutomi; Kaneto, Hideaki; Matsuoka, Taka‐aki; Kasami, Ryuichi; Kohno, Kenji; Nakatani, Yoichiro; Yamasaki, Yoshimitsu; Shimomura, Iichiro; Matsuhisa, Munehide

doi:10.1507/endocrj.k09e-140

Cited by 44 publications

(28 citation statements)

References 32 publications

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“…The adipocyte form, PPAR␥2, is induced in liver in the setting of traditional WD-induced hepatic steatosis, and, whereas selective elimination of PPAR␥2 by gene targeting reduces hepatic steatosis, its loss also worsens lipotoxicity and insulin resistance (28,43,50,53,68). Ligand-induced activation of PPAR␥ may also ameliorate hepatic ER stress (31,67). Our results suggest a nutritional switch that regulates hepatic PPAR␥ splice isoforms.…”

Section: Discussionmentioning

confidence: 72%

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

Garbow

Doherty

Schugar

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

151

156

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Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, Ezenwajiaku N, Cotter DG, Brunt EM, Crawford PA. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol 300: G956 -G967, 2011. First published March 31, 2011 doi:10.1152/ajpgi.00539.2010.-Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of longterm administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a highsimple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis. nutrient state; magnetic resonance spectroscopy; peroxisome proliferator activated receptor-␥; insulin resistance; unfolded protein response; x-box-binding protein-1 splicing; high-fat diets; fatty liver disease THERAPEUTIC USE OF REDUCED-CARBOHYDRATE diets has been extensively studied for the amelioration of a multitude of clinical states, including obesity and its metabolic complications, seizure disorders, and malignancies of the central nervous system (21,23,26,36,41,54,55,59,64). Nonetheless, the full scope of metabolic effects incurred by low-, and very low (ketogenic)-carbohydrate diets (KD) has only been preliminarily characterized. In wild-type mice, KDs result in weight loss and increased hepatic and myocardial fatty acid oxidation, compared with mice maintained on standard chow diets rich in polysaccharides (5,35,62). Whereas leptin-deficient obese (ob/ob) animals maintained on KD for 7 wk exhibit persistent weight gain, glucose tolerance and insulin resistance improve compared with ob/ob mice maintained on standard chow diet (3, 57). Collectively, encouraging preclinical and clinical studies of low-carbohydrate KDs have favored their continued study for anticonv...

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Section: Discussionmentioning

confidence: 72%

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

Garbow

Doherty

Schugar

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

151

156

View full text Add to dashboard Cite

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“…Loffler et al have also found significant down-regulation of ER stress genes in the livers from diabetic db/ db mice treated with rosiglitazone [10]. Yoshiuchi et al have reported that pioglitazone treatment suppressed ER stress in the liver by using ER-stress-activated indicator transgenic mice [28]. This is why they had suggested that the suppression of ER stress might explain, at least in part, the pharmacological effects of pioglitazone in reducing insulin resistance.…”

Section: Resultsmentioning

confidence: 99%

“…Secondly, the underlying molecular mechanism of how casein induces ER stress or how rosiglitazone attenuates this change was not clearly defined in our study. It may be possible that increased levels of serum adiponectin influenced the reduction of ER stress in the liver, [28]. Lastly, we did not quantify the degree of casein-induced ER stress and hepatocyte apoptosis.…”

Section: Casein Injection Induces Hepatic Er Stress and Rosiglitazonmentioning

confidence: 98%

Rosiglitazone attenuates casein-induced hepatic endoplasmic reticulum stress in Sprague-Dawley rats: a novel model of endoplasmic reticulum stress

Kang

Kim

et al. 2013

Endocr J

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“…UPR is an important tightly regulated response required for cellular homeostasis, and it intersects with many other pathways that are critical for glucose metabolism, glycogen synthesis, lipid metabolism, inflammation, and metabolic disease 45. Recent studies have shown that the UPR plays a role in liver disease,46, 47 that its activation is associated with hepatic insulin resistance and fatty acid flux,48, 49 and that the UPR mediator XBP1 can up‐regulate hepatic lipogenic factor 47, 50. Our study suggests that overexpression of MAN1A1 leads to steatosis, inflammation, and HCC formation, possibly through the UPR, perhaps evoking the transcriptional networks involved in hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

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α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)

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Pioglitazone Reduces ER Stress in the Liver: Direct Monitoring of in vivo ER Stress Using ER Stress-activated Indicator Transgenic Mice

Cited by 44 publications

References 32 publications

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

Rosiglitazone attenuates casein-induced hepatic endoplasmic reticulum stress in Sprague-Dawley rats: a novel model of endoplasmic reticulum stress

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

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