Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP) of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD) are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE) for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPARγ activation in hepatocytes and (ii) PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

[1]  M. Yeh,et al.  Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice , 2009, Journal of gastroenterology and hepatology.

[2]  N. Lee,et al.  A water-soluble extract of Petalonia binghamiae inhibits the expression of adipogenic regulators in 3T3-L1 preadipocytes and reduces adiposity and weight gain in rats fed a high-fat diet. , 2010, The Journal of nutritional biochemistry.

[3]  A. Bonen,et al.  Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane. , 2007, Prostaglandins, leukotrienes, and essential fatty acids.

[4]  R. Coleman,et al.  The role of lipid droplets in metabolic disease in rodents and humans. , 2011, The Journal of clinical investigation.

[5]  A. Guillouzo,et al.  Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver , 2010, PPAR research.

[6]  X. Su,et al.  Cellular fatty acid uptake: a pathway under construction , 2009, Trends in Endocrinology & Metabolism.

[7]  Y. Barak,et al.  Role for PPARγ in obesity‐induced hepatic steatosis as determined by hepatocyte‐ and macrophage‐specific conditional knockouts , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  A. Nederveen,et al.  Lipotoxicity and steatohepatitis in an overfed mouse model for non-alcoholic fatty liver disease. , 2011, Biochimica et biophysica acta.

[9]  Sean M. Hartig,et al.  Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is a Cell-Autonomous Regulator of Lipolysis Essential for Adipocyte Differentiation , 2012, Molecular and Cellular Biology.

[10]  Satoru Takahashi,et al.  Inhibition of Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (Fbw7α) Causes Hepatosteatosis through Krüppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ2 (PPARγ2) Pathway but Not SREBP-1c Protein in Mice* , 2011, The Journal of Biological Chemistry.

[11]  H. Tsukahara,et al.  Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors γ and α expressions in the liver of Wilson's disease. , 2012, Molecular Genetics and Metabolism.

[12]  Cheol-Young Park,et al.  Role of peroxisome proliferator‐activated receptor gamma agonist in improving hepatic steatosis: Possible molecular mechanism , 2012, Journal of diabetes investigation.

[13]  A. Vidal-Puig,et al.  Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome--an allostatic perspective. , 2010, Biochimica et biophysica acta.

[14]  Fuqiang Wen,et al.  Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPARγ/NF-κB pathway , 2012, Respiratory Research.

[15]  M. Yeh,et al.  MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes. , 2008, Journal of hepatology.

[16]  B. Sos,et al.  Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. , 2011, The Journal of clinical investigation.

[17]  公彦 松末.  肝臓の脂質蓄積における新たな制御メカニズム：肝PPARγ-fsp27シグナルの役割 , 2012 .

[18]  A. Bennett,et al.  Loss of Mitogen-activated Protein Kinase Phosphatase-1 Protects from Hepatic Steatosis by Repression of Cell Death-inducing DNA Fragmentation Factor A (DFFA)-like Effector C (CIDEC)/Fat-specific Protein 27* , 2011, The Journal of Biological Chemistry.

[19]  T. Ha,et al.  Zanthoxylum piperitum DC ethanol extract suppresses fat accumulation in adipocytes and high fat diet-induced obese mice by regulating adipogenesis. , 2012, Journal of nutritional science and vitaminology.

[20]  T. Fournier,et al.  PPARs and the placenta. , 2007, Placenta.

[21]  M. Birnbaum,et al.  PPARγ contributes to PKM2 and HK2 expression in fatty liver , 2012, Nature Communications.

[22]  A. Galli,et al.  PPARγ and Oxidative Stress: Con(β) Catenating NRF2 and FOXO , 2012, PPAR research.

[23]  N. Anderson,et al.  Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis , 2008, Pharmacological Reviews.

[24]  A. Ciccodicola,et al.  PPARG: Gene Expression Regulation and Next-Generation Sequencing for Unsolved Issues , 2010, PPAR research.

[25]  W. Stremmel,et al.  Uptake of long chain fatty acids is regulated by dynamic interaction of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts) , 2008, BMC Cell Biology.

[26]  Y. Kawano,et al.  Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease , 2013, Journal of Gastroenterology.

[27]  G. Shulman,et al.  Downregulation of ADIPOQ and PPARγ2 Gene Expression in Subcutaneous Adipose Tissue of Obese Adolescents With Hepatic Steatosis , 2010, Obesity.

[28]  G. Shulman,et al.  Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance , 2011, Diabetologia.

[29]  David A. Sass,et al.  Nonalcoholic Fatty Liver Disease: A Clinical Review , 2005, Digestive Diseases and Sciences.

[30]  P. Verkade,et al.  Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts. , 2006, Biochimica et biophysica acta.

[31]  H. Satoh,et al.  Hepatic steatosis with relation to increased expression of peroxisome proliferator-activated receptor-γ in insulin resistant mice. , 2013, Biological & pharmaceutical bulletin.

[32]  J. Wands,et al.  Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis. , 2008, Journal of hepatology.

[33]  Munn Sharon,et al.  Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity , 2012 .

[34]  T. Okumura.  Role of lipid droplet proteins in liver steatosis , 2011, Journal of Physiology and Biochemistry.

[35]  J. Hamilton,et al.  CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. , 2013, Biochemistry.

[36]  Y. Cha,et al.  Lactobacillus plantarum LG42 Isolated from Gajami Sik-Hae Inhibits Adipogenesis in 3T3-L1 Adipocyte , 2013, BioMed research international.

[37]  S. Miura,et al.  An increase in liver PPARγ2 is an initial event to induce fatty liver in response to a diet high in butter: PPARγ2 knockdown improves fatty liver induced by high-saturated fat. , 2011, The Journal of nutritional biochemistry.

[38]  M. Serio,et al.  Peroxisome proliferator-activated receptor gamma (PPARγ): Is the genomic activity the only answer? , 2010, Steroids.

[39]  J. M. Suh,et al.  PPARγ signaling and metabolism: the good, the bad and the future , 2013, Nature Medicine.

[40]  R. Seger,et al.  MAPK- Kinases as Nucleo-Cytoplasmic Shuttles for PPARγ , 2007, Cell cycle.

[41]  S. O’Rahilly,et al.  PPARγ and human metabolic disease , 2006 .

[42]  Zhenyuan Song,et al.  4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPARγ and accelerating ubiquitin–proteasome degradation , 2012, Molecular and Cellular Endocrinology.

[43]  Steven K. Gibb.  Toxicity testing in the 21st century: a vision and a strategy. , 2008, Reproductive toxicology.

[44]  L. Videla,et al.  Misregulation of PPAR Functioning and Its Pathogenic Consequences Associated with Nonalcoholic Fatty Liver Disease in Human Obesity , 2012, PPAR research.

[45]  In-kyu Lee,et al.  Scoparone inhibits adipocyte differentiation through down-regulation of peroxisome proliferators-activated receptor γ in 3T3-L1 preadipocytes. , 2013, Food chemistry.

[46]  F. Bellanti,et al.  Free radical biology for medicine: learning from nonalcoholic fatty liver disease. , 2013, Free radical biology & medicine.

[47]  M. Lazar,et al.  Endogenous Ligands for Nuclear Receptors: Digging Deeper* , 2010, The Journal of Biological Chemistry.

[48]  Chunxiang Zhang,et al.  Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid. , 2010, Molecular cell.

[49]  J. Seong,et al.  Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis , 2012, Proceedings of the National Academy of Sciences.

[50]  Salman Azhar,et al.  Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. , 2010, Future cardiology.

[51]  P. King,et al.  Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase , 2012, Proceedings of the National Academy of Sciences.

[52]  Kyongbum Lee,et al.  Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation , 2013, Wiley interdisciplinary reviews. Systems biology and medicine.

[53]  C. Mandarim-de-Lacerda,et al.  Peroxisome Proliferator-Activated Receptors-Alpha and Gamma Are Targets to Treat Offspring from Maternal Diet-Induced Obesity in Mice , 2013, PloS one.

[54]  Ajay C Donepudi,et al.  Enhanced Nrf2 Activity Worsens Insulin Resistance, Impairs Lipid Accumulation in Adipose Tissue, and Increases Hepatic Steatosis in Leptin-Deficient Mice , 2012, Diabetes.

[55]  Guidance on information requirements and chemical safety assessment , 2008 .

[56]  Soile Tapio,et al.  Supplementary table 1 , 2014 .

[57]  David M. Reif,et al.  ToxCast: Predicting Toxicity Potential Through High‐Throughput Bioactivity Profiling , 2013 .

[58]  Yoshitomo Hamuro,et al.  Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA , 2008, Nature.

[59]  J. Dekker,et al.  Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population , 2012, Journal of internal medicine.

[60]  Robert V Farese,et al.  Lipid droplets at a glance , 2009, Journal of Cell Science.

[61]  B. Neuschwander‐Tetri.  Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites , 2010, Hepatology.

[62]  K. Matsusue.  A physiological role for fat specific protein 27/cell death-inducing DFF45-like effector C in adipose and liver. , 2010, Biological & pharmaceutical bulletin.

[63]  Jibin Dong,et al.  Sphingomyelin Synthase 2 Activity and Liver Steatosis: An Effect of Ceramide-Mediated Peroxisome Proliferator-Activated Receptor &ggr;2 Suppression , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[64]  M. Febbraio,et al.  The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease , 2011, Experimental biology and medicine.

[65]  S. Mandrup,et al.  Molecular Mechanisms and Genome-Wide Aspects of PPAR Subtype Specific Transactivation , 2010, PPAR research.

[66]  N. Nowak,et al.  Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. , 2011, Metabolism: clinical and experimental.

[67]  Guowen Liu,et al.  Adiponectin activates the AMPK signaling pathway to regulate lipid metabolism in bovine hepatocytes , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[68]  G. Musso,et al.  Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). , 2009, Progress in lipid research.

[69]  N. Jafari,et al.  Transcription coactivator mediator subunit MED1 Is required for the development of fatty liver in the mouse , 2011, Hepatology.