Pathogenesisof NAFLD

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Published on March 6, 2014

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Pathogenesis of NAFLD : Pathogenesis of NAFLD AYASKANTA SINGH Introduction:  Introduction NASH was described : “alcoholic- like liver disease that develops in people who do not drink alcohol” Ludwig et al , J.mayo clin proc 1980 NAFLD : Defination Presence of steatosis ( accumulation of fat in excess of 5-10% of liver weight ) detected by Imaging/Histopathological study. Exclusion of secondary causes of fatty liver. PowerPoint Presentation: NAFLD has reached epidemic proportions . Prevalence in India- 24.5% Singh SP et al Trop Gastroenterol 2004 Pathophysiology of NAFLD not well understood . Multifactorial Associated with obesity, diabetes, and insulin resistance, Considered to be the liver manifestation of the metabolic syndrome . Several hypothesis Spectrum: Spectrum McCullough et al Clin . Liver Dis. 2004 The ‘2-hit’ hypothesis:  The ‘2-hit’ hypothesis Suggested by Day and James in 1998 . 1 st hit – Hepatic triglyceride accumulation or Steatosis 2 nd hit – Inflammatory cytokines/ adipokines , mitochondrial dysfunction and oxidative stress, which in turn lead to steatohepatitis and/or fibrosis. The traditional 2-hit hypothesis: The traditional 2-hit hypothesis The traditional 2-hit hypothesis: steatosis represents the ‘first hit’, which then sensitises the liver to injury mediated by ‘second hits’ Pathogenesis of hepatic steatosis : Pathogenesis of hepatic steatosis Dysregulation of fatty acid metabolism leads to steatosis . Disordered energy homoestasis . Accumulation of triglycerides (TG) are formed from the esterification of FFA and glycerol within the hepatocyte . PowerPoint Presentation: FFA accumulation : Lipolysis (hydrolysis of FFA and glycerol from triglyceride) within adipose tissue(64%) De novo lipogenesis (DNL) (26%) Dietary sources (15%). Donnelly KL et al, J Clin Invest 2005 FFA utilization : Beta –oxidation of fatty acids Re- esterification to TG and storage as lipid droplets, Packaged and exported as very low density lipoprotein (VLDL) PowerPoint Presentation: VLDL particles are formed by the incorporation of TG into apolipoprotein B ( apoB ) by microsomal transfer protein (MTP). Aberrant alterations of MTP/ apoB synthesis and secretion have been proposed as potential mechanisms. Adams LA ,CMAJ 2005 Obesity: Obesity Obesity and hepatic steatosis strongly correlated . Visceral fat more noxious than subcutaneous fat . Elevated levels of FFAs in plasma which leads increased hepatic uptake Increases splanchnic lipolysis in portal vein . Increasing visceral obesity results in increased production of pro inflammatory cytokines [TNF α , IL- 6, and CRP] and decreased production of protective adiponectin . G. Atzmon et al ,Hormone and Metabolic Research 2002 Lean NAFLD: Lean NAFLD The lean NAFLD approximately 13.2% of total NAFLD . Dyslipidemia present in 90% of lean NAFLD patients . IR present in 7.4% patient s of lean NAFLD . Compared to obese NAFLD, the severity of liver histopathology was significantly lower in patients with lean NAFLD . Kumar et al , Ind J of Endocrinology and Metabolism 2013 Insulin Resistance: Insulin Resistance Insulin resistance is a universal phenomenon in NAFLD G. C. Farrell et al., Hepatology 2002 Insulin resistance is intimately related to obesity Proposed Mechanism : Insulin suppress adipose tissue lipolysis . In situations of IR impaired suppression leads to increased efflux of FFA from adipose tissue . PowerPoint Presentation: Up -regulation of transcription factor Sterol Regulatory Element Binding Protein-1c (SREBP-1c), a key gene involved in DNL . Down regulation mitochondrial beta –oxidation of FFAs. In the liver, IR increased intracellular degradation of VLDL and apo B-100. PowerPoint Presentation: Forward vicious cycle Many abnormalities reported in NAFLD : FFAs , TNF- α , Nuclear factor kappa β (NF-k β ), Ceramide SOCS(suppressors of cytokine signaling ) Cytochrome CYP2E1 . Lipid metabolites like diacyl glycerol (DAG) . Interfere with insulin signalling cascade, and contribute to IR NAFLD : Beyond I R : NAFLD : Beyond I R Hepatic De novo Lipogenesis: Hepatic De novo Lipogenesis By product of hepatic gluconeogenesis and results in the synthesis of FFA s in the liver . Sensitive to insulin resistance Normally responsible for <5% of hepatic FFAs ,but IR states increases to about 20 % . PowerPoint Presentation: Nuclear transcription factors regulates Hepatic DNL The principal nuclear receptors are SREBP1 (sterol regulatory element binding protein1c) ChREBP (carbohydrate response element-binding protien ) LXR Alpha FXR ( Farnesoid X Receptor ) PPAR Gamma PPAR Alpha Mutations leads to hepatic steatosis ,observed in mice models . McPherson R,et al , Biochem Cell Biol 2004 Dietary factors: Dietary factors Dietary Fatty Acids Contribute to increased fatty acid influx into the liver . Trans fatty acid, derived from partial dehydrogenation of vegetable oils ( found in processed food) have a causative role in hepatic steatosis . Kim HJ et al ,J Lipid Res 2002 Fructose Increased consumption of high fructose corn syrup ( e.g soft drinks) is linked with insulin resistance syndrome. The hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion . Xiaosen Ouyang et al , Journal of Hepatology 2008 Pathogenesis of steatohepatitis: Pathogenesis of steatohepatitis Inflammatory cytokines FFA and lipotoxicity Adipokines Oxidative stress and mitochondrial dysfunction ,ER stress Bacterial overgrowth Inflammatory cytokines :  Inflammatory cytokines Steatosis associated with chronic hepatic inflammation . This effect is mediated by activation of the IKK-B/NF-KB signalling pathway. Activated directly by FFA . Increases pro-inflammatory mediators - TNF α , IL-1 α , IL-6 . Interferes with insulin signalling – IR . PowerPoint Presentation: Serum and hepatic levels of TNF- α elevated NASH patients, levels correlate with histological severity. Crespo J et al , Hepatology 2001 TNF- α promotes IR. Inhibition of TNF- α signalling improves IR and NASH. Serum IL-6 levels elevated in IR and NAFLD, which correlate with inflammation and fibrosis . Klover PJ, Endocrinology 2005 Cytokines can replicate all of the histological features of NASH, i.e neutrophil chemotaxis , hepatocyte apoptosis /necrosis , Mallory body formation and stellate cell activation. Day CP. Et al Gastroenterology 2006 FFA and lipotoxicity: FFA and lipotoxicity Increased levels of FFA - directly toxic to hepatocytes . Mechanisms : Leads to stimulation of TNF-α. Up-regulates cytochrome P450 isoenzymes , generation of ROS and lipid peroxidation . Up-regulates PPAR- α, which promotes FA oxidation but increases oxidative stress through dicarboxylic acid derivatives . Directly toxic to cellular membranes, forms toxic FA ethyl ethers and disruption of mitochondrial function . Modified 2-hit hypothesis: Modified 2-hit hypothesis The accumulation of FFA alone is sufficient to induce liver damage, without recourse for a second hit. Rather than being harmful, triglyceride accumulation in the form of steatosis may actually be protective by preventing FFA-induced inflammation and oxidative stress. Yamaguchi K, Hepatology 2007 Adipokines : Adipokines Adipose tissue - actively secreting endocrine organ. Adipokines ( adipocyte -derived peptides) :- leptin and adiponectin Adiponectin Anti-inflammatory ( antagonises TNF- α ) Increases insulin sensitivity Increases fatty acid β -oxidation . Serum adiponectin levels reduced in obesity, IR , diabetes mellitus, and metabolic syndrome . The administration of recombinant adiponectin improves biochemical and histological parameters of NAFLD in a murine model. Tomita K et al Hepatology 2008 PowerPoint Presentation: Leptin Role in pathogenesis is unclear . Satiety hormone , controls food intake and energy regulation . Involved with insulin signaling and regulation of glucose metabolism in peripheral tissues . Role in regulating the partitioning of fat between mitochondrial β -oxidation and triglyceride synthesis in the liver ???? Severe steatohepatitis develop in leptin -deficient (ob/ob) mice . Higher levels observed in obese and NAFLD patients which are regarded as states of leptin resistance . Huang XD et al , World J Gastroenterol 2008 Oxidative stress and mitochondrial dysfunction :  Oxidative stress and mitochondrial dysfunction Plays important role in progression . Increased FFA load β oxidation overwhelmed reactive oxygen species (ROS). ROS induce oxidative stress , activates inflammatory pathways causes mitochondrial damage . Elevated expression of hepatic microsomal FA oxidizing enzyme Cytochrome P450 (CYP2E1) -- observed in human and animal models of NASH and represents a potent source of ROS. Farrell GC et al , Hepatology 1998 PowerPoint Presentation: Mitochondrial Damage Structurally abnormal; they become ballooned and lose cristae ,inclusion bodies . Decrease in the activity of mitochondrial respiratory chain complexes , with a concomitant increase in mitochondrial ROS formation . Altered ATP homeostasis Bacterial overgrowth and endotoxin : Bacterial overgrowth and endotoxin Endotoxins are suspected in the pathogenesis of alcoholic steatohepatitis . Serum levels of bacterial endotoxin and LPS stimulate hepatic production of TNF-α, IL-6, and IL-8 and activate an inflammatory response that leads to hepatic necrosis . PowerPoint Presentation: Portal endotoxemia was believed to contribute to NASH associated with surgical jejunoileal bypass (performed in the past to treat obesity), the risk of which was reduced with antibiotics . Hocking MP, et al ,Dig Dis Sci 1998 Small intestinal bacterial overgrowth and increased gut permeability have been found more frequently in patients with NASH when compared with controls . Miele L et al , Hepatology 2009 PowerPoint Presentation: Revealed over-representation of Lactobacillus species and selected members of phylum Firmicutes A significant increase in fecal ester VOC in obese NAFLD patients Fibrosis /cirrhosis: Fibrosis /cirrhosis Fibrosis frequent histologic finding in advanced NAFLD. Exact pathogenesis unknown . Fibrosis : activation and proliferation of hepatic stellate cells in the subendothelial space of Disse secretion of extracellular matrix(ECM) components,i.e collagen types I and III Factors involved in fibrogenic process : inflammatory cytokines, angiotensin , alterations in the ECM, growth factors, and oxidative stress PowerPoint Presentation: Enhanced hepatic production of transforming growth factor- β (TGF- β ) --- activates stellate cells . Hyperinsulinemia associated with NAFLD may stimulate release of Platelet-derived growth factor (PDGF), Connective tissue growth factor (CTGF ) , Vascular endothelial growth factor (VEGF), Fibroblast growth factor and other cytokines . Genetic predisposition: Genetic predisposition Play an important role in hepatic steatosis progressing into NASH and cirrhosis . Polymorphisms in genes related to lipid metabolism, IR, oxidative stress, cytokines/ adipokines and fibrogenesis may all increase susceptibility to NASH development . SNP in the angiotensinogen and TGF- β 1 genes to be associated with advanced hepatic fibrosis in obese patients . Yoneda M,et al Liver Int 2009 Environmental factors : Environmental factors The third hit hypothesis: The third hit hypothesis ‘Third-hit’ has been added to reflect inadequate hepatocyte proliferation. In the healthy liver, cell death stimulates replication of mature hepatocytes which replace the dead cells and reconstitute normal tissue function. However oxidative stress, lipotoxicity inhibits the replication of mature hepatocytes which results in expansion of the hepatic progenitor cell (oval cell) population . Richardson MM,et al Gastroenterology 2007; PowerPoint Presentation: These HPCs are strongly correlated with fibrosis stage . Activation of these cells has also been implicated in hepatocellular carcinogenesis . Inappropriate proliferation of hepatocyte progenitors represents the proposed ‘third hit’ in NAFLD pathogenesis . PowerPoint Presentation: Jou j et al , Semin Liver Dis 2008 Conclusion : Conclusion The pathogenesis of NAFLD and NASH is a complex multi step process. Genetic factors obesity hyperinsulinemia and metabolic syndrome and environmental and dietary factors. Clinical profile varies . Recent advances in the understanding of pathogenesis of NAFLD can help in the development of potential therapeutic strategies . Impact steatosis and the subsequent progression to steatohepatitis Thank you: Thank you Thank you... Proposed pathogenesis of NASH. The likelihood of progression to advanced NASH/cirrhosis results from a complex interplay between genetic predisposition and the mechanisms described earlier.: Proposed pathogenesis of NASH. The likelihood of progression to advanced NASH/cirrhosis results from a complex interplay between genetic predisposition and the mechanisms described earlier. Oxidation of FFas: Oxidation of FFa s Mitochondrial beta oxidation Peroxisomal Beta oxidation PPAR Gamma provides key enzymes for these processes which leads to ATP production. Impaired FFA elimination: Impaired FFA elimination Intrahepatic FFAs are metabolized by two pathways . a) Esterified to VLDL particles ,excreted into systemic circulation . b) Mitochondrial Beta oxidation . Transmembrane Carrier families and entry of FFAs into liver: Transmembrane Carrier families and entry of FFA s into liver Influx of FFAs into hepatocytes is mediated by four transmembrane carrier families . Fatty acid transport proteins Fatty acid translocase Fatty acid binding protein and Caveolins The overexpression of these in mice models have shown to encourage hepatic steatosis . Ref….. LIPOGENIC ENZYMES :  LIPOGENIC ENZYMES Diacylglycerol Acyltransferase1 and 2 (DGAT1 and DGAT 2 ) Acetyl Co-A Carboxylase 1 and 2 (ACC1 and 2) PowerPoint Presentation: DGAT 1 and DGAT 2 enzymes catalyze the final step in triglyceride synthesis . DGAT 1 facilitates VLDL secretion while DGAT2 promotes hepatic lipid accumulation . Mice who over expresses DGAT2 develop increased hepatic steatosis . Inhibition of DGAT2 causes a marked reduction in hepatic TG content via downregulation of SREBP1 and upregulation of Beta oxidation of FFAs .

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