The mechanistic basis for the induction of hepatic steatosis by xenobiotics.

INTRODUCTION: Hepatic steatosis is the histological observation of numerous lipid inclusions due to an excess accumulation of triacylglycerols. They are a concern with new therapeutic candidates because they signify altered lipid metabolism that can progress to more serious liver toxicity. AREAS COVERED: This article is based on an article search using the PubMed database from 1987 to 2011 and confirms associations for several previously marketed drugs with four basic hepatocellular mechanisms. The article also describes how these mechanisms are controlled by master regulators of lipid metabolism, which include gene transcription factors, nuclear receptors, hormonal signaling, energy sensing proteins, endoplasmic reticulum stress signaling and certain key metabolic intermediates. EXPERT OPINION: Drug-induced hepatic steatosis is typically not detectable by conventional means other than invasive histological examinations. By understanding the basic mechanisms, key regulators and energy signaling systems of the liver, the investigator is better equipped to avoid xenobiotics with steatogenic potential in the drug discovery or early development process. There are now a number of methods for detecting this potential, specifically gene expression or metabolomic profiling and pathway analysis or mechanism-based in vitro systems.