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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with a wide disease spectrum
A recent study in mice has identified that the feed-forward cycle of continuous exposure to high-fat diet over two generations leads to a significantly higher degree of obesity, NAFLD, insulin and leptin resistance, and epigenetic modifications resulting in increased lipogenesis and ER stress in future generations (Li et al, 2011)
As detailed in this review, several components of the drug metabolism pathway are significantly affected in the presence of NAFLD
Summary
Reviewed by: Erik Eliasson, Karolinska Institute, Sweden Urs A. 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. 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 have endobiotic ligands including several lipids. 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. This review focuses on the complex interplay between NAFLD pathogenesis and drug metabolism.
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