Published online Jun 8, 2015. doi: 10.4254/wjh.v7.i10.1297
Peer-review started: January 18, 2015
First decision: February 7, 2015
Revised: February 21, 2015
Accepted: March 16, 2015
Article in press: March 18, 2015
Published online: June 8, 2015
Non-alcoholic fatty liver disease (NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as non-alcoholic fatty liver (NAFL) or simple steatosis, and non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms, such as, insulin resistance (IR), lipotoxicity, inflammation, oxidative stress, and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1 (GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion, inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted, GLP-1 is quickly degraded by dipeptidyl peptidase-4 (DPP-4). Therefore, DPP-4 inhibitors are able to extend the activity of GLP-1. Currently, GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors, such as the farsenoid X receptor, also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with immunomodulatory, anti-inflammatory, antiapoptotic, antioxidant and anti-fibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as, TGR5, farnesoid X receptor-α, or the small heterodimeric partner. Finally, pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion, inhibit mucosal adherence by bacteria, and stimulate host immunity. In animal models, probiotics prevent obesity, decrease transaminase levels, and improve IR and liver histology in NASH.
Core tip: Non-alcoholic fatty liver disease (NAFLD) is an important health care problem. The pathophysiology of NAFLD and non-alcoholic steatohepatitis (NASH) and their progression are multifactorial and complex processes, where multi-parallel simultaneous hits derived from the gut and adipose tissue promote a pro-inflammatory response and liver injury. All of these represent attractive therapeutic targets. Pharmacological agents such as glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, ursodeoxycholic acid, obeticholic acid and probiotics need to be explored in clinical trials specifically for treating NAFLD and NASH.