Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine‐choline deficient diet by CCAAT/enhancer‐binding protein homologous protein deficiency

Toriguchi, Kan; Hatano, Etsuro; Tanabe, Katsuaki; Takemoto, Kenji; Nakamura, Kojiro; Koyama, Yukinori; Seo, Satoru; Taura, Kojiro; Üemoto, Shinji

doi:10.1111/jgh.12481

Cited by 55 publications

(48 citation statements)

References 45 publications

(103 reference statements)

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“…In addition, an excess of sucrose and trans-fat is supplemented in the formula of the MCD diet. These components exacerbated fat accumulation and hepatocellular damage of MCD diet-fed mice within 2-4 weeks [35, 55, 56]. Prolonged MCD feeding resulted in fibrosis (8 weeks) and the appearance of malignant neoplastic nodules in 3-6 months [55].…”

Section: Characteristics Of Currently Available Rodent Nash-hcc Modelsmentioning

confidence: 99%

“…These components exacerbated fat accumulation and hepatocellular damage of MCD diet-fed mice within 2-4 weeks [35, 55, 56]. Prolonged MCD feeding resulted in fibrosis (8 weeks) and the appearance of malignant neoplastic nodules in 3-6 months [55]. The tumorigenicity may be potentiated by exposure to DEN during MCD diet feeding [55].…”

Section: Characteristics Of Currently Available Rodent Nash-hcc Modelsmentioning

confidence: 99%

“…Prolonged MCD feeding resulted in fibrosis (8 weeks) and the appearance of malignant neoplastic nodules in 3-6 months [55]. The tumorigenicity may be potentiated by exposure to DEN during MCD diet feeding [55]. Notably, the body weight of MCD diet-fed mice is often lower than controls, and there is no insulin resistance.…”

Section: Characteristics Of Currently Available Rodent Nash-hcc Modelsmentioning

confidence: 99%

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Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

2016

Oncotarget

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Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver disorders with fat accumulation from simple fatty liver, nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis and NAFLD/NASH-associated hepatocellular carcinoma (HCC). NASH is a progressive form of NAFLD and requires medical attention. One of 5-10 NASH patients may progress to end-state liver disease (ESLD or cirrhosis) in 5-10 years; meanwhile, life-threatening complications of ESLD and HCC account for major mortality. An increasing burden of NAFLD in clinics, elucidation of its pathogenesis and progression, and assessment of the efficacy of potential therapeutics demand reliable animal models. Most NASH-associated HCC occurs in cirrhotic subjects; however, HCC does appear in NASH patients without cirrhosis. Lipotoxicity, oxidant stress, insulin resistance, endoplasmic reticulum stress, altered adipokine and lymphokine profiles and gut microbiome changes affect NAFLD progression and constitute key pathobiologic interplays. How these factors promote malignant transformation in a microenvironment of steatotic inflammation and fibrosis/cirrhosis, and lead to development of neoplasms is one of critical questions faced in the hepatology field. The present review summarizes the characteristics of emerging rodent NASH-HCC models, and discusses the challenges in utilizing these models to unveil the mysteries of NASH-associated HCC development.

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Section: Characteristics Of Currently Available Rodent Nash-hcc Modelsmentioning

confidence: 99%

Section: Characteristics Of Currently Available Rodent Nash-hcc Modelsmentioning

confidence: 99%

Section: Characteristics Of Currently Available Rodent Nash-hcc Modelsmentioning

confidence: 99%

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Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

2016

Oncotarget

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“…Chop deletion protects mice from various hepatocyte-specific challenges, including bile duct ligation (Tamaki et al 2008), acetaminophen (Uzi et al 2013), alcohol feeding (Ji et al 2005), and diet-induced steatohepatitis (Rinella et al 2011;Toriguchi et al 2014). In contrast to the beneficial effect of Chop deficiency, Chop −/− mice fed a methionine-choline-deficient (MCD) diet display increased liver damage (Soon et al 2010), possibly explained by a net accumulation of activated macrophages due to decreased death in the absence of CHOP (Malhi et al 2013).…”

Section: Chop/ddit3/gadd153mentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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“…In absence of CHOP, both cells and animals are protected against various pharmacological and physiological insults (Tabas and Ron, 2011). It has been shown that CHOP deficiency attenuates cholestasis-induced liver fibrosis and methionine-choline-deficient (MCD) diet-induced steatohepatitis, fibrosis, and carcinogenesis in mice (Tamaki et al, 2008; Toriguchi et al, 2013). In a murine model of intragastric ethanol feeding, CHOP null mice have remarkable absence of hepatocellular apoptosis, but no protection against alcohol-induced steatosis (Ji et al, 2005).…”

Section: Upr and Hepatic Lipid Homeostasismentioning

confidence: 99%

ER stress and hepatic lipid metabolism

Zhou

Liu

2014

Front. Genet.

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The endoplasmic reticulum (ER) is an important player in regulating protein synthesis and lipid metabolism. Perturbation of ER homeostasis, referred as “ER stress,” has been linked to numerous pathological conditions, such as inflammation, cardiovascular diseases, and metabolic disorders. The liver plays a central role in regulating nutrient and lipid metabolism. Accumulating evidence implicates that ER stress disrupts lipid metabolism and induces hepatic lipotoxicity. Here, we review the major ER stress signaling pathways, how ER stress contributes to the dysregulation of hepatic lipid metabolism, and the potential causative mechanisms of ER stress in hepatic lipotoxicity. Understanding the role of ER stress in hepatic metabolism may lead to the identification of new therapeutic targets for metabolic diseases.

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Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine‐choline deficient diet by CCAAT/enhancer‐binding protein homologous protein deficiency

Cited by 55 publications

References 45 publications

Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

Physiological/pathological ramifications of transcription factors in the unfolded protein response

ER stress and hepatic lipid metabolism

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