A little orphan runs to fat: The orphan receptor small heterodimer partner as a key player in the regulation of hepatic lipid metabolism

Nonalcoholic fatty liver disease (NAFLD) encompasses a disease spectrum ranging from relatively benign “pure” fatty liver to steatohepatitis [nonalcoholic steatohepatitis (NASH)] with inflammation and fibrosis, which can progress to cirrhosis and hepatocellular cancer. Because it is closely associated with metabolic syndrome and insulin resistance, NAFLD is already the leading cause of elevated liver function tests in Western countries, and we should be prepared to see more of it (including NASH at the more severe end of this spectrum) in the near future. Although considerable progress has been made with the use of insulin sensitizers such as metformin and glitazones, no generally accepted pharmacological treatment of NAFLD/NASH is available.2 As some of these therapeutic shortcomings have to be attributed to our limited understanding of the pathogenesis of NAFLD,3 studies such as the present article by Huang et al.,4 which shed more light on the pathogenesis and uncover novel potential therapeutic targets in NAFLD, are very welcome. Ligand-activated nuclear receptors (NRs) serve as metabolic sensors that can integrate metabolic and hormonal signals to changes in gene expression.5 As such, NRs play a key role in the regulation of the hepatic metabolism of bile acids, lipids, hormones, and drugs,6 and this makes them attractive drug targets for the treatment and prevention of liver diseases. Intriguingly, NRs not only regulate metabolic processes but can also modulate inflammation and fibrosis, two key ingredients for the development of progressive liver disease. Small heterodimer partner (SHP; NR0B2) is an exceptional member of the NR family because it lacks a DNA binding domain and known ligands (i.e., it is still a true orphan receptor), but it directly interacts with a range of other conventional NRs and negatively regulates their transcriptional activity by acting as an inducible corepressor.5-7 It is expressed in several tissues, with relatively high expression in the liver, heart, and pancreas and also in skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). 7 In the liver, SHP suppresses bile acid uptake and synthesis, the latter by the inhibition of liver receptor homolog-1 (LRH-1; NR5A2) transactivation of the gene encoding the key bile acid synthetic enzyme, cytochrome P450, family 7, subfamily A, polypeptide 1 (Cyp7a1). 6 Because bile acids themselves induce SHP through the farnesoid X receptor (FXR; NR1H4), this pathway provides a negative feedback loop, helping to prevent hepatic bile acid overload (Fig. 1). More recent studies have identified a broader role for SHP in the regulation of energy production in BAT,8 glucose homeostasis,9 and hepatic triglyceride metabolism.10 In order to fully appreciate the (patho)physiological consequences of SHP manipulation, it is important to consider its multiple hepatic and extrahepatic actions and the fact that in rare instances SHP can also act as a transcriptional activator.11 In this elegant study, Huang et al.4 shed more light on the role of SHP in the regulation of hepatic lipid metabolism and its potential role in the pathogenesis of NAFLD. Using transgenic and knockout mouse models for SHP, previous studies have already noted a role for SHP in hepatic lipid metabolism,8-10,12,13 although the underlying mechanisms have remained incompletely understood. The authors now were able to demonstrate that SHP expression was induced in genetic [leptin-deficient ob/ob (OB / ) mice] and dietary (high-sucrose/high-fat diet) mouse models of NAFLD, providing a good rationale for targeting SHP. The underlying molecular mechAbbreviations: ACC, acetyl-CoA carboxylase; apo, apolipoprotein; BA, bile acids; BAT, brown adipose tissue; ChREBP, carbohydrate response element binding protein; Chol, cholesterol; Cyp, cytochrome P450; FA, fatty acid; FAS, fatty acid synthase; FATP, fatty acid transport protein; FXR, farnesoid X receptor; G6P, glucose-6-phosphatase; Glc, glucose; HNF-4, hepatocyte nuclear factor-4; HSL, hormone-sensitive lipase; JNK, c-jun N-terminal kinase; LPL, lipoprotein lipase; LRH-1, liver receptor homolog-1; LXR, liver X receptor; MTP, microsomal triglyceride transfer protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NR, nuclear receptor; oxid. , fatty acid oxidation; OB / , leptin-deficient ob/ob; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1 , peroxisome proliferator-activated receptorcoactivator 1 ; PPAR, peroxisome proliferator-activated receptor; SHP, small heterodimer partner; SREBP-1c, sterol regulatory element binding protein-1c; TG, triglyceride; UCP-1, uncoupling protein 1; VLDL, very low density lipoprotein; WAT, white adipose tissue. Supported by grants from the Austrian Science Foundation (P18613, F3008B0S) and the Austrian Ministry of Science and Education. Address reprint requests to: Michael Trauner, M.D., Professor of Medicine and Molecular Hepatology, Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. E-mail: michael.trauner@meduni-graz.at; fax: 43-316-385-7560. Copyright © 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.21801 Potential conflict of interest: Nothing to report.