Fast break on the fat brake: Mechanism of peroxisome proliferator-activated receptor-δ regulation of lipid accumulation in hepatocytes
Authors: Danielle B. Andrews, Jeffrey B. Schwimmer, Joel E. Lavine
Journal: Hepatology (2008)

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 NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; insig-1, insulin-induced gene 1; SREBP, sterol-responsive element-binding protein. 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 (α, γ, and δ) 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. PPAR-α enhances 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 PPAR-γ regulates promotion of lipid accumulation and regulation of differentiation of adipocytes, in the liver, the primary role involves regulation of the inflammatory response in resident macrophages and downstream effects of inflammatory mediators on ameliorating fibrosis in activated stellate cells. In fact, the improvement in NASH histopathology found in human subjects treated with the PPAR-γ agonist pioglitazone is likely due to this anti-inflammatory effect, because patients generally gain weight due to overall fat accumulation during treatment.8 The function of the ubiquitous PPAR-δ has been more of a mystery, but it now appears to be the most promising of all PPAR targets for NASH due to its profound regulatory actions on fat, muscle, heart, and liver. This PPAR is activated by polyunsaturated fatty acid ligands such as eicosapentaenoic acid, to enhance fatty acid oxidation, enhance adaptive thermogenesis, reduce macrophage inflammatory responses, and increase high-density lipoproteins.9, 10 Further utility of PPAR-δ may be due to its recently demonstrated activation by the ligand 4-hydroxynonenal, a product of oxidative stress, which is thought to be a second critical hit in hepatocytes rendered vulnerable to injury by fat accumulation.11 Hepatotoxic xenobiotics or other NASH-related causes of increased reactive oxygen species provoke an intracellularly mediated activation of PPAR-δ, which initiates a downstream cascade of detoxification genes. In this issue of HEPATOLOGY, Qin et al. elegantly illustrate the mechanism of action by which PPAR-δ exerts its effect on lipid depletion in hepatocytes, both in vitro and in vivo. Through a series of experiments in which PPAR-δ activity is increased by pharmacological agonists or augmented through transduction, they demonstrate that hormone action is transcriptionally mediated through up-regulation of the gene for insulin-induced gene 1 (insig-1), which is shown to have a noncanonical PPAR-binding response element (Fig. 1A). They also demonstrate that insig-1 brakes a sterol-responsive element binding protein (SREBP) precursor in the endoplasmic reticulum, preventing the precursor from undergoing maturation in the Golgi. Thus, less mature SREBP is available to bind to upstream transcriptional regulatory elements for key genes in lipogenesis (Fig. 1B). The authors further demonstrate that infection of obese diabetic mice with adenovirus vector delivering PPAR-δ resulted in amelioration of hepatic steatosis.12 Proposed mechanism for PPAR-δ–mediated suppression of hepatic lipogenesis. (A) Schematic of PPAR-δ agonist effect on insig-1 expression. Agonists such as unsaturated fatty acids enter hepatocytes and bind to PPAR-δ. The ligand-protein complex translocates to the nucleus and binds to the distal one of two noncanonical PPAR-δ response elements upstream of the insig-1 structural gene. Complex binding up-regulates insig-1 transcription and translation. (B) Effect of insig-1 on regulation of hepatic lipogenesis. Insig-1 bound to endoplasmic reticulum effectively brakes release of SREBP precursor bound to SREBP cleavage-activating protein (SCAP). Relative paucity of insig-1, in the absence of specific oxysterols or free fatty acids, results in mobilization of SREBP precursor/SCAP to the Golgi, where SREBP undergoes proteolytic cleavage. Mature SREBP binds to DNA response elements upstream of key genes regulating lipogenesis. A recent phase I/II double-blind, randomized trial of a PPAR-δ agonist as therapy for certain metabolic abnormalities in obese men demonstrated that the PPAR-δ treatment group had significant improvements in quantitative liver fat and diminished urinary markers of oxidative stress.13 Further development and testing of pure PPAR-δ agonists in the treatment of NASH, insulin resistance, metabolic syndrome, or obesity is eagerly awaited, particularly among those of us who wish to work out less and eat more.