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Hepatic Steatosis

Hepatic Steatosis. Chen-Yu Wang 052209. Nonalcoholic fatty liver disease (NAFLD). Most common cause of liver dysfunction in the US. Affects >30% or 70 million people in the US. -Fatty liver (Steatosis). -Nonalcoholic steatohepatitis. -Liver fibrosis and cirrhosis.

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Hepatic Steatosis

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  1. Hepatic Steatosis Chen-Yu Wang 052209

  2. Nonalcoholic fatty liver disease (NAFLD) Most common cause of liver dysfunction in the US Affects >30% or 70 million people in the US -Fatty liver (Steatosis) -Nonalcoholic steatohepatitis -Liver fibrosis and cirrhosis

  3. The Progression of NAFLD 20~30% of NAFLD patients develop nonalcoholic steatohepatitis 5~15% of NASH patients develop fibrosis and cirrhosis 10% of liver transplants in the US are done for cirrhosis related to NAFLD

  4. Steatosis and insulin resistance obesity Insulin resistance Compensatory hyperinsulinemia Lipolysis in adipose tissue Adipocyte uptake of fatty acids Hepatic TG synthesis Fatty acids to be delivered to liver Hepatic fat oxidation

  5. Two-Hit Theory Malaguarnera et al, J. Mol Med, 2009

  6. Steatosis Characterized by the accumulation of triglyceride in hepatocytes Can be a result of : Increased fat delivery Increased fat synthesis Reduced fat oxidation Reduced fat export Associated with obesity, insulin resistance, type 2 diabetes, arterial hypertension, and heperlipidemia

  7. Steatosis and insulin resistance 59% 26% 15% Tilg and Moschen, Cell, 2008

  8. Genetics of NAFLD Prevalence of NAFLD differs in racial groups African American (24%) <European American (33%) <Hispanics (45%) SNPs involved in NAFLD: PNPLA3 PPARGC1A (PPAR-g coactivator 1a) Adiponectin CLOCK

  9. NAFLD and SREBP1c A transcription factor which activates genes required for lipogenesis SREBP1c transgenic mice develop NAFLD

  10. NAFLD and XBP1 A Key regulator of the mammalian unfolded protein response (UPR) Hepatic XBP1 level is induced upon high-carbohydrate feeding Lee et al, Science, 2008

  11. NAFLD and PPAR-g The deficiency of liver-specific PPAR-g improves fatty liver in ob/ob mice ob/ob PPAR-g- ob/ob PPAR-g+ Matsusue et al, JCI, 2003

  12. NAFLD and PPAR-g Matsusue et al, JCI, 2003

  13. NAFLD and PPAR-g Hepatic PPAR-g controls the expression of lipogenic genes in ob/ob mice Matsusue et al, JCI, 2003

  14. NAFLD and PPAR-a Stienstra et al, Endocrinology, 2007

  15. NAFLD and PPAR-a Enzymes required for b-oxidation

  16. NAFLD and FXR Mainly expressed in the liver, the gut , the kidney and the adrenal cortex Bile acids are natural FXR ligand Chenodeoxycholic acid > lithocholic acid = deoxycholic acid > cholic acid Function as a monomer or a heterodimer with retinoid X receptor (RXR)

  17. NAFLD and FXR CA lowers hepatic TGs Watanabe et al, JCI, 2004

  18. NAFLD and FXR CA attenuates LXR agonist–induced lipogenesis in vivo. Watanabe et al, JCI, 2004

  19. NAFLD and Adiponectin A cytokine secreted by adipose tissue Serum adiponectin level decreased in obesity, insulin resistance, type II diabetes, and nonalchoholic steatohepatitis AdipoR1 is expressed primarily in the adipose tissue, while AdipoR2 is expressed primarily in the liver Adiponectin increases insulin sensitivity and ameliorates fatty liver diseases in obese ob/ob mice

  20. NAFLD and Adiponectin Tilg and Hotamisligil, Gastroenterology, 2006

  21. NAFLD and mir-122 Esau et al, Cell Metabolism, 2006

  22. NAFLD and mir-122 Esau et al, Cell Metabolism, 2006

  23. NAFLD and other microRNA Cheung et al, Hepatology, 2008

  24. Diagnosis of NAFLD Biopsy Ultrasound and Magnetic Resonance Spectroscopy (MRS) Biomarkers: Increased: M30 antigen (cleaved cytokeratin-8) Serum prolidase enzymes (SPEA) Dehydroepiandrosterone (DHEA) Cytokeratin-18 IL-6 Pentraxin3 Decreased: Leptin

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