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

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

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

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

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

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

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

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

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

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

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

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

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

NAFLD and PPAR-a Enzymes required for b-oxidation

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)

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

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

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

NAFLD and Adiponectin Tilg and Hotamisligil, Gastroenterology, 2006

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

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

NAFLD and other microRNA Cheung et al, Hepatology, 2008

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