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