Fast break on the fat brake: Mechanism of peroxisome proliferator‐activated receptor‐δ regulation of lipid accumulation in hepatocytes

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in developed nations, representing the consequence of caloric excess and poor nutrition in the setting of a sedentary lifestyle. NAFLD encompasses a spectrum of findings histologically, ranging from isolated hepatocellular macrovesicular steatosis to more pronounced changes found in nonalcoholic steatohepatis (NASH) including steatosis, mixed lobular inflammation, ballooning injury, and perisinusoidal fibrosis. NASH can progress to cirrhosis or hepatocellular carcinoma. Most cases of NAFLD are associated with visceral obesity and insulin resistance, often with hyperlipidemia and hypertension. NASH is thus considered a hepatic manifestation of metabolic syndrome.1-3 Metabolic syndrome is a pathophysiologic consequence of energy imbalance between diverse organs and tissues. Brown and white adipose tissue, skeletal muscle, and liver play a critical role in fatty acid metabolism and energy homeostasis, coordinated through a variety of circulating endocrine and paracrine factors. These factors orchestrate complex transcriptional programs with target cells, mediating the balance between energy utilization and storage. White adipose tissue is primarily responsible for storage of triglyceride, which is released as free fatty acid in the blood during times of need. Brown adipose tissue, along with skeletal muscle, serves to dissipate energy in times of excess in a process called adaptive thermogenesis. Adaptive thermogenesis uncouples the process of oxidative phosphorylation, with adenosine triphosphate generation as the product, from heat production mediated through uncoupling proteins. In effect, adaptive thermogenesis is the body’s protective mechanism against obesity. Obesity represents the consequence of an overwhelmed adaptive response. Understanding of the intracellular mechanisms coordinating oxidation to energy uncoupling is becoming better understood with recognition of a subclass of nuclear hormone receptors called peroxisome proliferator-activated receptors (PPARs). 4 PPARs compose three isoforms of 48 human nuclear hormone receptors, which are related by common structural domains for ligand-activation and DNA binding. They regulate responses to environmental cues by binding ligands such as fatty acids (or fatty acid derivatives such as oxidation products and prostaglandins) in a cell-specific and ligand-specific manner. Receptor-ligand complexes, formed in the cytoplasm, translocate to the nucleus as obligate heterodimers (with the retinoid X receptor) where they bind to PPAR-specific response elements. Binding of complex to such elements affect globally coordinated transcriptional response programs in diverse genes controlling lipogenesis or fatty acid catabolism, uptake, or release. In this way, dynamic responses maintain homeostasis. Characterization of receptor responses is complicated by the many variables which affect receptor profiles, including species, animal strain, age or developmental stage, time of day, tissue and cell type, functional polymorphisms, and a multitude of receptor coactivators and repressors. Also clear is the demonstration that action of a single nuclear hormone receptor is influenced in context of other nuclear hormone receptors. However, despite the many differences found between mice and humans in the quantity, location, and temporal appearance of PPARs, they clearly play a major role in hepatic fat metabolism.5 This renders them major targets for therapeutic interventions in the metabolic syndrome and NASH.6 The three isoforms of PPARs ( , , and ) are all found in the liver, albeit distributed in more or less abundant quantities in different liver cell types playing a role in NASH pathogenesis. PPARenhances combustion of fatty acids in hepatocytes by up-regulating beta-oxidation. The hypolipidemic effects of bezafibrate and congeners is mediated through this generation of ketone bodies to support energy needs during fasting.7 Although PPARregulates promotion of lipid accumulation and regulation of differentiation of adipocytes, in the liver, the primary role involves regulation of the inflammatory reAbbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; insig-1, insulininduced gene 1; SREBP, sterol-responsive element-binding protein. Address reprint requests to: Joel E. Lavine, 200 West Arbor Drive, MC 8450, San Diego, CA 92103-8450. E-mail: jolavine@ucsd.edu; fax 619-543-7537. Copyright © 2008 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.22505 Potential conflict of interest: Nothing to report.