PPARα Expression Protects Male Mice from High Fat–Induced Nonalcoholic Fatty Liver1–3

Abdelmegeed, Mohamed A.; Yoo, Seong Ho; Henderson, Lauren E.; Gonzalez, Frank J.; Woodcroft, Kimberley J.; Song, Byoung Joon

doi:10.3945/jn.110.135210

Cited by 235 publications

(230 citation statements)

References 41 publications

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“…In the current study, knockdown of Ppara also resulted in increased inflammation, necrosis, matrix remodeling, and evidence of stellate cell activation and fibrosis after feeding 70% HF diets relative to Wt mice. These data are consistent with previous studies on development of NASH in adult Ppara À/À mice fed high-fat diets 7 and similar to our previously published data on progression of alcoholic liver pathology in these mice. 8 Interestingly, and consistent with previous studies of NASH progression in the rat, 26 Cd44 mRNA, which encodes the major cell surface hyaluronan (HA) receptor, was significantly up-regulated in 70% HF diet-fed Ppara À/À mice.…”

Section: Discussionsupporting

confidence: 83%

“…Deletion of Ppara has previously been shown to result in progression of liver pathology beyond simple steatosis to inflammation and fibrosis in adult mouse models of alcoholic and nonalcoholic liver disease. 6,7,22 The current data suggest a similar pattern of pathology when high polyunsaturated fat diets are fed to Ppara À/À mice beginning during early development. Increased evidence of oxidative stress, as indicated by increased oxidized glutathione/ reduced glutathione ratio and 4-Hne protein adducts, was observed in Ppara À/À compared to Wt mice fed 70% HF diets.…”

Section: Discussionmentioning

confidence: 54%

“…6 It was shown that this knockout resulted in enhanced steatosis, lipid peroxidation, and inflammation compared to wild-type (Wt) mice fed highfat liquid diets for 3 weeks. 7 More recently, we have made mice with a double knockout of Ppara À/À and the glutathione-S-transferase enzyme Gsta4 À/À (dKO). 8 Gsta4 is a detoxification enzyme that eliminates reactive electrophilic a,b unsaturated aldehydes, such as the lipid peroxidation product 4-hydroxynonenal (4-Hne).…”

mentioning

confidence: 99%

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Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis

Ronis

Mercer

Engi

et al. 2017

The American Journal of Pathology

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We established a mouse model of developmental nonalcoholic steatohepatitis (NASH) by feeding a high polyunsaturated fat liquid diet to female glutathione-S-transferase 4-4 (Gsta4 À/À )/peroxisome proliferator activated receptor a (Ppara À/À ) double knockout 129/SvJ mice for 12 weeks from weaning. We used it to probe the importance of lipid peroxidation in progression of NASH beyond simple steatosis. Feeding Gsta4 À/À /Ppara À/À double-knockout (dKO) mice liquid diets containing corn oil resulted in a percentage fatedependent increase in steatosis and necroinflammatory injury (P < 0.05). Increasing fat to 70% from 35% resulted in increases in formation of 4-hydroxynonenal protein adducts accompanied by evidence of stellate cell activation, matrix remodeling, and fibrosis (P < 0.05). Comparison of dKO mice with wild-type (Wt) and single knockout mice revealed additive effects of Gsta4 À/À and Ppara À/À silencing on steatosis, 4-hydroxynonenal adduct formation, oxidative stress, serum alanine amino transferase, expression of tumor necrosis factor alpha, Il6, interferon mRNA, and liver pathology (P < 0.05). Induction of Cyp2e1 protein by high-fat diet was suppressed in Gsta4 À/À and dKO groups (P < 0.05). The dKO mice had similar levels of markers of stellate cell activation and matrix remodeling as Ppara À/À single KO mice. These data suggest that lipid peroxidation products play a role in progression of liver injury to steatohepatitis in NASH produced by high-fat feeding during development but appear less important in development of fibrosis. Pediatric nonalcoholic fatty liver disease is a prevalent chronic liver pathology observed in 9.6% of children and up to 38% of those that are obese.1 Fatty liver disease has been reported in morbidly obese children as young as 2 to 3 years old.1,2 In approximately 30% of cases, pediatric liver pathology progresses from simple steatosis to nonalcoholic steatohepatitis (pNASH), characterized by necroinflammation and development of fibrosis.3 pNASH is now the major cause of liver transplant in pediatric populations. 4 However, despite the emergence of pNASH as a major pediatric disease, little is known regarding the molecular mechanisms underlying the development of NASH in children and there are no good developmental animal models that mimic the natural etiological setting in which pNASH develops clinically.A nutritional model of adult NASH was developed in Sprague-Dawley rats by Lieber et al, 5 in which liver pathology developed after feeding a 71% high-fat liquid diet. This high-fat feeding model was also applied to adult mice lacking the transcription factor peroxisome

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

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Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis

Ronis

Mercer

Engi

et al. 2017

The American Journal of Pathology

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“…Furthermore, it can limit interleukin (IL)-1-associated C-reactive protein expression [50,52] . In this regard, it has been shown that PPARα deficient mice are susceptible to hepatic steatosis and NASH [53][54][55] . The current concept is that PPARα activation may prevent these abnormalities [50,53] .…”

Section: Introductionmentioning

confidence: 99%

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Kostapanos

Kei²,

Elisaf³

2013

WJH

131

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Non-alcoholic fatty liver disease (NAFLD) is a common health problem with a high mortality burden due to its liver-and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Impaired hepatic fatty acid (FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors (PPARs) are involved in lipid and glucose metabolic pathways. The novel concept is that the activation of the PPARα subunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibraterelated PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis. These include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet, T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent. In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.

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“…They act as intracellular sensors for free fatty acids and cholesterol metabolism and are major regulators of cell metabolism as well as cell differentiation and cellular homeostasis (185,186). PPARα promotes fatty acid mitochondrial β-oxidation, thereby decreasing steatosis (187)(188)(189). Farnesoid X receptor (FXR) acts as a sensor for bile acids and inhibits bile acid synthesis if the bile acid pool is increased, thereby protecting hepatocytes from the toxic effect of bile acids (190).…”

Section: Different Underlying Pathophysiologies and Therapeutic Implimentioning

confidence: 99%

Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis

et al. 2017

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PPARα Expression Protects Male Mice from High Fat–Induced Nonalcoholic Fatty Liver1–3

Cited by 235 publications

References 41 publications

Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis

Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis

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