Molecular Interactions between NAFLD and Xenobiotic Metabolism

Abstract

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a complex multifactorial disease characterized by metabolic deregulations that include accumulation of lipids in the liver, lipotoxicity, and insulin resistance. The progression of NAFLD to non-alcoholic steatohepatitis and cirrhosis, and ultimately to carcinomas, is governed by interplay of pro-inflammatory pathways, oxidative stress, as well as fibrogenic and apoptotic cues. As the liver is the major organ of biotransformation, deregulations in hepatic signaling pathways have effects on both, xenobiotic and endobiotic metabolism. Several major nuclear receptors involved in the transcription and regulation of phase I and II drug metabolizing enzymes and transporters also have endobiotic ligands including several lipids. Hence, hepatic lipid accumulation in steatosis and NAFLD, which leads to deregulated activation patterns of nuclear receptors, may result in altered drug metabolism capacity in NAFLD patients. On the other hand, genetic and association studies have indicated that a malfunction in drug metabolism can affect the prevalence and severity of NAFLD. This review focuses on the complex interplay between NAFLD pathogenesis and drug metabolism. A better understanding of these relationships is a prerequisite for developing improved drug dosing algorithms for the pharmacotherapy of patients with different stages of NAFLD.

Intermittent calorie restriction largely counteracts the adverse health effects of a moderate‐fat diet in aging C57BL/6J mice

“…PXR is a ligand‐activated nuclear receptor that, upon activation, forms a heterodimer with RXR. This complex is not only activated by exogenous toxins but has also been shown to responds to endobiotics like bile acids and steroid hormones 79, 80. Previous studies have shown that PXR activation in mice induces fatty acids uptake via upregulation of Cd36 , which is one of the 148 consistently regulated genes.…”

Experimental Nonalcoholic Steatohepatitis Increases Exposure to Simvastatin Hydroxy Acid by Decreasing Hepatic Organic Anion Transporting Polypeptide Expression

“…Although genetic variation clearly plays a role in the occurrence of ADRs, other factors such as liver diseases are also known to alter drug pharmacokinetics and contribute to the occurrence of ADRs (Verbeeck, 2008;Merrell and Cherrington, 2011;Gandhi et al, 2012;Naik et al, 2013). Liver diseases that impair hepatic function may require dose adjustments to maintain drug concentrations within the therapeutic window and avoid ADRs (Delcò et al, 2005;Verbeeck, 2008).…”

Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease

“…Another location where ROS is generated is in microsomes. FFA is the inductive agent of P450-2E1, which occupies an important position in the cascade of ROS and lipid peroxidation generation (6). In microsomes, FFAs are easily oxidized and degraded into acyl-CoA.…”

“…Excessive oxidative stress derives from mitochondrial dysfunction and iron overload. The unceasingly increased ROS, and the product of oxidative stress, results in the rapid depletion of ATP, DNA injury, instability of protein and release of inflammatory factors, sequentially break cellular completeness of structure and function, which promotes the development of NAFLD (6,10).…”