Class III and Class IV the Orphans

Class III receptors form homodimers like class I receptors, but bind direct repeats like Class II receptors. Class IV receptors act as monomers and bind extended core sties. While Class I receptors bind steroid hormones, and Class II receptors bind metabolites of nutrients, no pattern has yet emerged for the ligands of Class III or Class IV nuclear receptors. In fact, most of these receptors are orphans with no potential ligands identified. The strictest definition of an endogenous ligand requires not only high affinity binding, but also appropriate in vivo concentrations for dynamic regulation of activity. The molecules that have been proposed to bind Class III and Class IV receptors fall short of the definition of an endogenous ligand. These molecules may play an important endogenous role other than activation. One possibility is that these molecules stabilize the receptor. This seems most plausible for the Class IV receptors, which function as monomers, and therefore are not stabilized by dimerization. Another possibility that cannot be excluded is that Class III and Class IV receptors are regulated by means other than ligand binding and have no endogenous ligand. It has been suggested that ancient orphan receptors may have evolved to acquire ligand-mediated activation.42,43

Hepatic nuclear factor-4 (HNF-4) is a Class III nuclear hormone receptor.158 There are two isotypes: HNF-4alpha and HNF-4gamma.20,25 However, HNF-4alpha has been studied more extensively. HNF-4alpha is expressed in the liver, small intestine and pancreatic beta-cells where it regulates both lipid and glucose metabolism.158 In the liver, HNF-4alpha transcriptionally up regulates apoA1, the most abundant apolipoprotein in HDL, and an important player in reverse cholesterol transport.58 HNF-4alpha also regulates other apolipoproteins, including apoCIII and apoAIV5,90 and genes involved in bile acid formation (cyp7a, cyp8b),30,32 lipid homeostasis, and glucose production.98

Mutations in HNF-4alpha result in type 1 mature onset diabetes of the young (MODY1) due to the importance of HNF-4alpha in the regulation of insulin transcription in pancreatic beta-cells.147 MODY is characterized by impaired insulin production with normal insulin sensitivity and is usually noninsulin requiring at the time of diagnosis.133 HNF-4alpha does not directly bind the insulin promoter but interacts with other transcription factors such as HNF-1alpha, which binds the insulin promoter directly.40 HNF-4alpha acts as a co-activator of HNF-1alpha increasing the transcription of HNF-1alpha target genes upon binding. MODY has also been attributed to mutations in HNF-1alpha.147 The importance of the HNF-4apha/HNF-1 alpha interaction has been illuminated by the investigation of HNF-4alpha mutations that cause MODY1. One such mutant, HNF-4alpha R127W, retains its ability to directly activate gene transcription and bind HNF-1alpha, but is unable to act as a co-activator for HNF-1alpha.146

In vitro binding assays show fatty acyl-CoA thioesters binding to HNF-4alpha, although the in vivo significance of this interaction is questionable.19,61,157 Conversely, there is strong evidence that phospholipids bind to and stimulate the Class IV nuclear hormone receptor, LRH-1.87,103,129 The phospholipid concentration in the nucleus is far higher than the Km, which although consistent with the constitutive activity of LRH-1, falls short of the definition of an endogenous ligand, because there is no dynamic regulation.45,70 The importance of phospholipid binding in vivo may be stabilization and not activation. LRH-1 is constitutively active, but is regulated by the dynamic availability of inactivating heterodimer partners such as SHP. Thus, it is plausible that LRH-1 is stabilized by phospholipid binding to the ligand pocket, but achieves dynamic regulation via dimerization.

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  • Niina M
    What is a cardiovascular disease of class II or class IV?
    9 months ago

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