Stress Signaling in the Methionine-Choline–Deficient Model of Murine Fatty Liver Disease

Soon, Russell K.; Yan, Jenny; Grenert, James P.; Maher, Jacquelyn J.

doi:10.1053/j.gastro.2010.07.046

Cited by 46 publications

(44 citation statements)

References 50 publications

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“…Consistent with our HFD data, MCD diet-fed Chop Ϫ/Ϫ mice developed significantly greater steatohepatitis both histologically and by ALT elevation, than wild type controls. This is consistent with a published study in which Chop Ϫ/Ϫ mice developed greater liver injury, inflammation, and steatosis upon MCD diet challenge (40). Thus, the sensitizing effects of CHOP to steatohepatitis were independent of obesity, being present both in the HFD-fed mice and the MCD diet-fed mice.…”

Section: Discussionsupporting

confidence: 81%

C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis

Malhi¹,

Kropp²,

Clavo³

et al. 2013

Journal of Biological Chemistry

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Background:We hypothesized that C/EBP homologous protein mediates hepatocyte apoptosis in nonalcoholic steatohepatitis. Results: Paradoxically, Chop deletion protects from steatohepatitis by inducing apoptosis in activated macrophages. Conclusion: CHOP-dependent macrophage apoptosis in NASH highlights the cell type-specific complexity of the ER stress response. Significance: Therapeutic manipulation of mediators of ER stress response may have opposite effects in different cell populations; therefore, such studies should be interpreted cautiously.

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Section: Discussionsupporting

confidence: 81%

C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis

Malhi¹,

Kropp²,

Clavo³

et al. 2013

Journal of Biological Chemistry

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“…For example, genetic modification and dietary deficiency models, such as the methionine-choline deficient model, result in hepatic lipid accumulation and robust pathology in the absence of obesity (1,21,24,31,32,33,57,65,68). Studies that have used ad libitum consumption of diets high in saturated fats or simple carbohydrates, show development of NAFLD but suffer from lack of much progression of injury beyond simple steatosis despite long feeding periods and are complicated by differences in caloric intake (52,56,69).…”

Section: Discussionmentioning

confidence: 99%

“…Characterized by initial fat accumulation (steatosis) in up to 70% of obese patients (68), NAFLD pathology can progress to include inflammation, apoptosis, necrosis, and fibrosis (nonalcoholic steatohepatitis, NASH) and ultimately cirrhosis and liver cancer (14). While nutrition and physical activity are clearly major factors in NAFLD development and progression, the exact role of diet composition in this process remains unclear (14,40).…”

mentioning

confidence: 99%

Dietary fat source alters hepatic gene expression profile and determines the type of liver pathology in rats overfed via total enteral nutrition

Ronis

Baumgardner

Marecki

et al. 2012

Physiological Genomics

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TM. Dietary fat source alters hepatic gene expression profile and determines the type of liver pathology in rats overfed via total enteral nutrition. Physiol Genomics 44: 1073-1089, 2012. First published September 18, 2012 doi:10.1152/physiolgenomics.00069.2012.-To determine if dietary fat composition affects the progression of nonalcoholic fatty liver disease (NAFLD), we overfed male Sprague-Dawley rats low (5%) or high (70%) fat diets with different fat sources: olive oil (OO), corn oil (CO), or echium oil (EO), with total enteral nutrition (TEN) for 21 days. Overfeeding of the 5% CO or 5% EO diets resulted in less steatosis than 5% OO (P Ͻ 0.05). Affymetrix array analysis revealed significant differences in hepatic gene expression signatures associated with greater fatty acid synthesis, ChREBP, and SREBP-1c signaling and increased fatty acid transport (P Ͻ 0.05) in the 5% OO compared with 5% CO group. The OO groups had macrosteatosis, but no evidence of oxidative stress or necrosis. The 70% CO and 70% EO groups had a mixture of micro-and macrosteatosis or only microsteatosis, respectively; increased oxidative stress; and increased necrotic injury relative to their respective 5% groups (P Ͻ 0.05). Oxidative stress and necrosis correlated with increasing peroxidizability of the accumulated triglycerides. Affymetrix array analysis comparing the 70% OO and 70% CO groups revealed increased antioxidant pathways and lower expression of genes linked to inflammation and fibrosis in the 70% OO group. A second study in which 70% OO diet was overfed for 50 days produced no evidence of progression of injury beyond simple steatosis. These data suggest that dietary fat type strongly influences the progression of NAFLD and that a Mediterranean diet high in olive oil may reduce the risk of NAFLD progressing to nonalcoholic steatohepatitis. nonalcoholic steatohepatitis; fatty acid; lipid peroxidation; SREBP-1c; ChREBP NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is increasingly recognized as a component of "metabolic syndrome," a cluster of pathologies associated with obesity (16). Characterized by initial fat accumulation (steatosis) in up to 70% of obese patients (68), NAFLD pathology can progress to include inflammation, apoptosis, necrosis, and fibrosis (nonalcoholic steatohepatitis, NASH) and ultimately cirrhosis and liver cancer (14). While nutrition and physical activity are clearly major factors in NAFLD development and progression, the exact role of diet composition in this process remains unclear (14, 40).Research in this area has been hampered by lack of an animal model that mimics the natural course and etiological background of NAFLD observed clinically (7, 40). In general, nutritionally relevant models in which obesity has been achieved as a result of ad libitum feeding of diets high in sugars, such as sucrose and fructose or in saturated fats, have resulted in simple steatosis with limited evidence of progressive injury (37,52,69). Moreover, uncontrolled differences in caloric intake and species and strain differen...

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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). As all of these studies were performed with ubiquitous Chop deletion, mechanistic insight is limited.…”

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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Stress Signaling in the Methionine-Choline–Deficient Model of Murine Fatty Liver Disease

Cited by 46 publications

References 50 publications

C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis

C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis

Dietary fat source alters hepatic gene expression profile and determines the type of liver pathology in rats overfed via total enteral nutrition

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

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