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 have been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may results 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 are more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 are 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 drug metabolizing enzymes and transporters. We also discuss the potential mechanisms underlying these alterations.

RNA N6-methyladenosine: a promising molecular target in metabolic diseases

“…NAFLD is the most common cause of chronic liver disease among children and adults all over the world [93][94][95], which is characterized by steatosis, ballooning degeneration, and fatty retention of liver parenchyma cells with no history of excessive alcohol intake or other known liver disease [96]. The pathological character of NAFLD is caused by metabolic dysregulation of de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and triglycerides export [97,98]. Previous studies have found that m 6 A alteration is highly related to the development of NAFLD [34,99,100].…”

Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack

“…Dysregulated immune responsiveness is central to the development and progression of NAFLD (9,10). In obesity, both liver resident (e.g., Kupffer cells, [KC], hepatic stellate cells, [HSC], hepatocytes) and infiltrating immune cells (e.g., neutrophils, dendritic cells [DC], natural killer [NK] cells, NKT cells, blood monocytes, T cells, B cells, and macrophages) contribute to NAFLD development and progression via systemic and tissue inflammatory mediator production (e.g., interleukin [IL]-17A, IL-6, tumor necrosis factor [TNF], IL-1β) (5,11).…”

“…Thus, it is not surprising that several pharmacological drugs that target metabolic and inflammatory and molecular mechanisms important in NAFLD progression are currently being examined (188). Hepatic lipid accumulation is an initial driver of NAFLD pathogenesis (9,84). Intuitively, use of therapeutic drugs that target lipid metabolism is actively pursued.…”

Gut Microbiota Mediates the Protective Effects of Andrographolide Inhibits Inflammation and Nonalcoholic Fatty Liver Disease(NAFLD) in High-Fat Diet induced ApoE(-/-) Mice

“…Similarly, we also confirmed that AG could prevent hepatosteatosis induced by the HFD through decreasing NF-κB, C/EBPβ and PPAR-γ in the liver and HEPG2 cells. Cobbina E et al found that the presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors in NAFLD (47). Chen HW et al (48) and Li F et al (49) found AG inhibit IL-1, IL-6 and TNF-α-induced inflammation in vivo and in vitro disease models.…”