Peroxisome Proliferator-Activated Receptor α Protects against Obesity-Induced Hepatic Inflammation

Stienstra, Rinke; Mandard, Stéphane; Patsouris, David; Maass, Cathy; Kersten, Sander; Müller, Michael

doi:10.1210/en.2007-0014

Cited by 175 publications

(131 citation statements)

References 36 publications

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“…As such, many PPARα target genes are involved in mitochondrial and peroxisomal β-oxidation of fatty acids [93]. Numerous studies of PPARα−/− mice have shown that fasting or high-fat feeding of these mice results in abnormal lipid accumulation in hepatocytes, which is consistent with a crucial role for PPARα in hepatic lipid metabolism [114] and [115]. In addition, in normal rats, high-fat feeding-induced steatosis was related to PPARα downregulation, presumably mediated by increased circulating free fatty acid [116].…”

Section: Peroxisome-proliferator-activated Receptors (Ppars)mentioning

confidence: 87%

“…Furthermore, in wild-type mice, HFD significantly increased the hepatic and adipose expression of numerous genes involved in inflammation. This effect was amplified in PPARα−/− mice and reduced in wild-type by treatment with the PPARα ligand Wy-14643, suggesting an anti-inflammatory role of PPARα in liver and adipose tissue [115]. In agreement with this, in a model of NASH, tranilast (that inhibits the action of the fibrogenic transforming growth factor-beta, TGF-β) attenuated hepatic inflammation, downregulated TNF-α expression, and up-regulated PPARα [119].…”

Section: Peroxisome-proliferator-activated Receptors (Ppars)mentioning

confidence: 97%

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From the metabolic syndrome to NAFLD or vice versa?

Vanni

Bugianesi

Kotronen

et al. 2010

Digestive and Liver Disease

437

351

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The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10-25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH.Abbreviations ALT, alanine aminotransferase; BMI, body mass index; CVD, cardiovascular disease; FFA, free fatty acids; HDL, high density lipoprotein; 1H-MRS, proton magnetic resonance spectroscopy; IDF, International Diabetes Federation; LDL, low density lipoprotein; NAFLD, nonalcoholic fatty liver disease; SNP, single nucleotide polymorphism; VLDL, very low density lipoprotein IntroductionThe metabolic syndrome is a cluster of metabolic and cardiovascular risk factors which predicts diabetes and cardiovascular disease (CVD) better than any of its individual components [1]. The latest definition of the metabolic syndrome by International Diabetes Federation (IDF) includes abdominal obesity defined by increased waist circumference (≥94 cm in men and ≥80 cm in women) and two or more of the following features: elevated blood pressure, fasting glucose or triglyceride concentrations, or low HDL cholesterol [1]. The term nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis [2] and [3]. NAFLD can be considered the hepatic manifestation of the metabolic syndrome. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation and/or fibrosis which can lead to cirrhosis, liver failure and hepatocellular carcinoma. In contrast to t...

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Section: Peroxisome-proliferator-activated Receptors (Ppars)mentioning

confidence: 87%

Section: Peroxisome-proliferator-activated Receptors (Ppars)mentioning

confidence: 97%

From the metabolic syndrome to NAFLD or vice versa?

Vanni

Bugianesi

Kotronen

et al. 2010

Digestive and Liver Disease

437

351

View full text Add to dashboard Cite

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“…These functions may be impaired in both small and large offspring and fit in with epidemiological data indicating an increase risk of later metabolic disease in both small (Eriksson et al 2003a, 2003b, Min et al 2007 and large infants (Gillman et al 2003, Leong et al 2003, Danielzik et al 2004). PPARA has a well-documented role in hepatic lipid metabolism (Stienstra et al 2007), but its role in adipose tissue and relationship to birth weight are less clear. Previous studies investigating the role of fetal programming in the female offspring of mice fed a high unsaturated fat diet during pregnancy have demonstrated increased PPARA protein in liver along with decreased hepatic triglyceride concentrations (Zhang et al 2005).…”

Section: Pparg2 and Amentioning

confidence: 99%

Influence of birth weight on gene regulators of lipid metabolism and utilization in subcutaneous adipose tissue and skeletal muscle of neonatal pigs

Williams¹,

Marten²,

Wilson³

et al. 2009

Reproduction

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Epidemiological studies suggest that low-birth weight infants show poor neonatal growth and increased susceptibility to metabolic syndrome, in particular, obesity and diabetes. Adipose tissue development is regulated by many genes, including members of the peroxisome proliferator-activated receptor (PPAR) and the fatty acid-binding protein (FABP) families. The aim of this study was to determine the influence of birth weight on key adipose and skeletal muscle tissue regulating genes. Piglets from 11 litters were ranked according to birth weight and 3 from each litter assigned to small, normal, or large-birth weight groups. Tissue samples were collected on day 7 or 14. Plasma metabolite concentrations and the expression of PPARG2, PPARA, FABP3, and FABP4 genes were determined in subcutaneous adipose tissue and skeletal muscle. Adipocyte number and area were determined histologically. Expression of FABP3 and 4 was significantly reduced in small and large, compared with normal, piglets in adipose tissue on day 7 and in skeletal muscle on day 14. On day 7, PPARA and PPARG2 were significantly reduced in adipose tissue from small and large piglets. Adipose tissue from small piglets contained more adipocytes than normal or large piglets. Birth weight had no effect on adipose tissue and skeletal muscle lipid content. Low-birth weight is associated with tissue-specific and time-dependent effects on lipid-regulating genes as well as morphological changes in adipose tissue. It remains to be seen whether these developmental changes alter an individual's susceptibility to metabolic syndrome.

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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%

“…Interestingly, PPARα agonism reversed steatohepatitis in mice, suggesting a potential curative role against NASH [56] . This benefit might be attributed to a downregulated expression of inflammatory genes [55] . Also, PPARα activation may reverse fibrosis by reducing the expression of fibrotic markers and the number of stellate cells [56] .…”

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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Peroxisome Proliferator-Activated Receptor α Protects against Obesity-Induced Hepatic Inflammation

Cited by 175 publications

References 36 publications

From the metabolic syndrome to NAFLD or vice versa?

From the metabolic syndrome to NAFLD or vice versa?

Influence of birth weight on gene regulators of lipid metabolism and utilization in subcutaneous adipose tissue and skeletal muscle of neonatal pigs

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

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