Table 1.

The rationale of current management approaches to the treatment of nonalcoholic fatty liver disease.

Intervention/drug class	Example	Rationale
Weight reduction/nutritional	Diet/exercise Orlistat, sibutramine	Weight loss improves insulin sensitivity; improves the metabolic profile
supplementation	Bariatric surgery n-3 polyunsaturated fatty acids	Decreased free fatty acid lipotoxicity in hepatocytes; Hepatic PPAR-α activation; suppresses hepatic de novo lipogenesis; antioxidant and anti-inflammatory effects
Antioxidants	Vitamin E N-acetylcysteine	Oxidative stress, directly or through cytokine release, contributes to inflammatory cell recruitment, perpetuation of liver injury and hepatic fibrogenesis; N-acetylcysteine is a glutathione prodrug
Cytoprotective agents	Ursodeoxycholic acid	Membrane stabilizing properties, antiapoptosis
Anticytokine treatment	Pentoxifylline	TNF-α levels are increased in NASH; TNF-α impairs insulin sensitivity and is involved in hepatic inflammatory cell recruitment in NASH. Pentoxifylline reduces TNF-α production and secretion.
Insulin sensitizers	Metformin	Promotes weight loss; improves hepatic insulin sensitivity; activates AMP-activated kinase and consequent hepatic fatty acid ß-oxidation
	Thiazolidinediones	PPAR-γ agonists improve peripheral and hepatic insulin sensitivity; increase adiponectin levels; have anti-inflammatory and antifibrotic effects
	Glucagon-like protein-1 -receptor agonist	Insulin secretagogue; reduces appetite; upregulates hepatic PPAR-α mRNA and downregulates SREBP-1 expression; reduces free fatty acid flux to the liver
	Nateglinide	Insulin secretagogue; upregulates hepatic PPAR-α and adiponectin receptor R2 mRNA expression
Lipid-lowering drugs	Gemfibrozil	Hyperlipidaemia is a component of the metabolic syndrome
	Fenofibrate, bezafibrate atorvastatin, pravastatin	Some have anti-inflammatory, antifibrogenic and antioxidant effects. Fibrates promote hepatic fatty acid ß-oxidation through activation of hepatic PPAR-α
Angiotensin converting enzyme inhibitors	Losartan	Renin-angiotensin blockade reduces experimental hepatic fibrosis; Telmisartan has partial PPAR-γ agonist properties
Endocannabinoid antagonists	Rimonabant	Reduce hepatic lipogenesis; antifibrotic properties; lowers TNF-a; increases serum adiponectin

PPAR: peroxisome proliferators activated receptor; TNF: tumour necrosis factor; SREBP-1: sterol regulatory element binding protein 1.