Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD

The pregnane X receptor drives sexually dimorphic hepatic changes in lipid and xenobiotic metabolism in response to gut microbiota in mice.

The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathologies, but the hepatic sensors and effectors of microbial signals are not well defined. By comparing publicly available liver transcriptomics data from conventional vs. germ-free mice, we identified pregnane X receptor (PXR, NR1I2) transcriptional activity as strongly affected by the absence of gut microbes. Microbiota depletion using antibiotics in Pxr <sup>+/+</sup> vs Pxr <sup>-/-</sup> C57BL/6J littermate mice followed by hepatic transcriptomics revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis suggested that microbiota-PXR interaction controlled fatty acid and xenobiotic metabolism. We confirmed that antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in the liver from Pxr <sup>+/+</sup> but not Pxr <sup>-/-</sup> male mice. These findings identify PXR as a hepatic effector of microbiota-derived signals that regulate the host's sexually dimorphic lipid and xenobiotic metabolisms in the liver. Thus, our results reveal a potential new mechanism for unexpected drug-drug or food-drug interactions. Video abstract

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants.

Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis

Piezoelectric aluminum nitride resonator for oscillator

International audienceThis work investigates properties of the thin film elongation acoustic resonator (TFEAR) operating at MHz frequencies in air. This resonator is composed of a piezoelectric layer of aluminum nitride (AlN) sandwiched between two aluminum electrodes (Al). TFEAR works in the extensional mode excited via AlN d31 piezoelectric coefficient. A 3D-finite element method analysis (FEM) using ANSYSreg software has been performed to model static modal and harmonic behavior of the TFEAR. In order to consider insertion losses into the substrate, equivalent electrical models based on modified Butterworth-Van Dyke (MBVD) circuit have been improved by adding extra dissipative elements. Thus, a whole model for the on-wafer characterization set-up is given, allowing for automatic de-embedding of the present TFEAR equivalent circuit. Quality factor Q as high as 2500 in air have been recorded with motional resistance lower than 400 Omega. A first oscillator based on a TFEAR resonator was also designed and tested

Piezoelectric aluminum nitride resonator for oscillator

International audienceThis work investigates properties of the thin film elongation acoustic resonator (TFEAR) operating at MHz frequencies in air. This resonator is composed of a piezoelectric layer of aluminum nitride (AlN) sandwiched between two aluminum electrodes (Al). TFEAR works in the extensional mode excited via AlN d31 piezoelectric coefficient. A 3D-finite element method analysis (FEM) using ANSYSreg software has been performed to model static modal and harmonic behavior of the TFEAR. In order to consider insertion losses into the substrate, equivalent electrical models based on modified Butterworth-Van Dyke (MBVD) circuit have been improved by adding extra dissipative elements. Thus, a whole model for the on-wafer characterization set-up is given, allowing for automatic de-embedding of the present TFEAR equivalent circuit. Quality factor Q as high as 2500 in air have been recorded with motional resistance lower than 400 Omega. A first oscillator based on a TFEAR resonator was also designed and tested

Piezoelectric aluminum nitride resonator for oscillator

International audienceThis work investigates properties of the thin film elongation acoustic resonator (TFEAR) operating at MHz frequencies in air. This resonator is composed of a piezoelectric layer of aluminum nitride (AlN) sandwiched between two aluminum electrodes (Al). TFEAR works in the extensional mode excited via AlN d31 piezoelectric coefficient. A 3D-finite element method analysis (FEM) using ANSYSreg software has been performed to model static modal and harmonic behavior of the TFEAR. In order to consider insertion losses into the substrate, equivalent electrical models based on modified Butterworth-Van Dyke (MBVD) circuit have been improved by adding extra dissipative elements. Thus, a whole model for the on-wafer characterization set-up is given, allowing for automatic de-embedding of the present TFEAR equivalent circuit. Quality factor Q as high as 2500 in air have been recorded with motional resistance lower than 400 Omega. A first oscillator based on a TFEAR resonator was also designed and tested

Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPAR-α and insulin-dependent signalling in hepatocytes

International audienc

Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes

BACKGROUND: The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-gamma (PI3Kgamma) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kgamma in the cardiovascular system suggest that PI3Kgamma plays a role in atherosclerosis. METHODS AND RESULTS: Here, we demonstrate that a specific PI3Kgamma inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E-deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor-deficient mice. Furthermore, PI3Kgamma levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor-deficient mice transplanted with wild-type or PI3Kgamma-deficient bone marrow demonstrated that functional PI3Kgamma in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kgamma activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. CONCLUSIONS: These data identify PI3Kgamma as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment