Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.

Keywords: Non-alcoholic fatty liver disease; cytochrome P450; diabetes; drug metabolizing enzymes; non-alcoholic steatohepatitis; steatosis; transporters.

Figure 1

The progressive stages of NAFLD (non-alcoholic fatty liver disease). The benign form of NAFLD, NAFL (non-alcoholic fatty liver), progresses to NASH (non-alcoholic steatohepatitis) with or without fibrosis. Subsequently, NASH leads to cirrhosis and eventually hepatocellular carcinoma (HCC). NASH may progress to HCC without cirrhosis.

Figure 2

Major components of the metabolic syndrome. The presence of at least three of these components define the presence of metabolic syndrome.