Peroxisome Proliferator–Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

Lalloyer, Fanny; Wouters, Kristiaan; Baron, Morgane; Caron, Sandrine; Vallez, Emmanuelle; Vanhoutte, Jonathan; Baugé, Eric; Shiri-Sverdlov, Ronit; Hofker, Marten H.; Staels, Bart; Tailleux, Anne

doi:10.1161/atvbaha.110.220525

Cited by 68 publications

(50 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22,23 LDLR or ApoE single-knockout mice developed some of the NAFLD characteristics [24][25][26] but generally failed to broadly reflect the whole spectrum of NAFLD key features. As such, ApoE À / À mice on a fat-and cholesterol-enriched diet developed hepatic inflammation but only mild steatosis.…”

Section: Discussionmentioning

confidence: 99%

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

Kampschulte

Stöckl

Langheinrich

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease has been linked to cardiovascular diseases and atherosclerosis. The aim of the current study was to characterize the hepatic pathology leading to fibrosis and tumors in a murine model of atherosclerosis.Male apolipoprotein E/low-density lipoprotein receptor double-knockout mice (AL) mice were fed with a high fat and high cholesterol western diet for 35 weeks (AL mice on WD). Protein and mRNA analysis as well as micro-computed tomography (micro-CT) were performed to assess oxidative stress, liver damage, inflammation, fibrosis, signaling pathways, vascularization, and tumorigenesis. Controls were chosen to distinguish between genetically and dietary effects in steatohepatitis and associated tumorigenesis. Hepatic inflammation and dyslipidemia were increased in AL mice on WD compared with wild-type mice on WD. Uniquely, AL mice on WD showed a spontaneous development of tumors (30% of cases) and thickening of intrahepatic vessel walls. Functionally relevant underlying signaling pathways such as NF-kB, Stat3, JNK, and AKT were differentially regulated between AL and wild-type mice on WD. Micro-CT was capable of visualizing and quantitatively distinguishing tumor neovascularization from vascularization in non-neoplastic liver tissue. AL mice on WD diet represent a novel model combining atherosclerosis and nonalcoholic fatty liver disease. Signaling pathways of liver cell damage and compensatory liver regeneration in combination with enhanced inflammation appear to be crucial for the spontaneous development of tumors in AL mice on WD. Micro-CT represents a new and powerful technique for the ultrastructural and three-dimensional assessment of the vascular architecture of liver tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

Kampschulte

Stöckl

Langheinrich

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Fenofibrate prevented from high-fat diet-induced hepatic TG accumulation [72][73][74][75] . Consequently, all histological findings of NAFLD, including hepatic steatosis, necroinflammation and collagen deposition, were reversed [72][73][74] .…”

Section: Mechanistic Implicationsmentioning

confidence: 96%

“…Inhibition of the liver expression of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 may help explain this benefit [75] . This action is PPARα-dependent [75] . Anti-inflammatory properties of fenofibrate imply a protective effect against NASH.…”

Section: Clinical Evidencementioning

confidence: 99%

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

Kostapanos

Kei²,

Elisaf³

2013

WJH

131

View full text Add to dashboard Cite

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.

show abstract

“…As far as mice models of NASH are concerned, APOE2 mice fed a western diet showed decreased hepatic macrophage accumulation, which precedes lipid accumulation within hepatocyte, and expressive reduction of lipotoxicity after treatment with fenofibrate. A marked reduction in the expression of proinflammatory genes, great expression of genes implicated in β-oxidation and the suppression of procollagen type 1 expression underlie these findings [56,57] . Total PPAR-gamma activation by rosiglitazone counters insulin resistance, but do not manage to reduce NAFLD in HF mouse models.…”

Section: Targeting Ppars To Treat Nafldmentioning

confidence: 96%

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Souza-Mello¹

2015

WJH

153

View full text Add to dashboard Cite

and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs. AbstractLately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal)

show abstract

Peroxisome Proliferator–Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

Cited by 68 publications

References 34 publications

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

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

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Contact Info

Product

Resources

About