MicroRNA-122: A New Player in the Negative Regulation of LH Receptor Expression by the LH Receptor mRNA Binding Protein (LRBP)

Abstract

The LH receptor (LHR) plays an essential role in mediating LH actions in the steroidogenic cells of the ovary (theca, granulosa, and luteal cells) and testis (Leydig cells). It belongs to the G protein-coupled superfamily of receptors with seven transmembrane domains (1) and it is one of the most studied peptide hormone receptors. After extensive characterization of its hormone binding properties in the early to mid 1970s (2–10), in the ensuing 40 years or so, tremendous progress has been made in understanding various functions of the LHR, including the regulation of cellular signaling (11–14), expression of steroidogenic acute regulatory protein (StAR), the protein that transports cholesterol to the inner mitochondrial membrane for side-chain cleavage (P450scc, CYP11A) (14–17), endocytic and selective delivery of exogenous cholesterol to the steroidogenic cells mediated by low-density lipoprotein receptor, and scavenger receptor class B, type, respectively (18–21), and the events connected with the mobilization of cholesterol from the intracellular stores (22, 23) and the cellular cholesterol trafficking (17, 24). However, relatively less is known about the molecular and cellular regulation of LHR expression (11, 12). Until recently, based on the available data, it was generally believed that LHR expression is primarily regulated at the level of gene transcription (1, 11). In recent years, however, the seminal studies carried out by Dr Jerry Menon's laboratory at the University of Michigan have led to the realization that LHR is also subject to posttranscription (25, 26). In fact, the overwhelming evidence now suggests that these mechanisms are major contributors to the LH-induced down-regulation of LHR. Initial studies reported by Menon and colleagues demonstrated that the expression of mevalonate kinase (MVK), a key enzyme involved in cholesterol biosynthesis, that catalyzes the conversion of mevalonic acid to 5-phosphomevalonic acid, is up-regulated under the conditions that promote the repression of the LHR expression (27–29). The follow-up studies demonstrated that MVK can directly bind to the coding region of LHR mRNA and inhibits its translational capacity (27–31); because of this specialized function, MVK was renamed by the Menon laboratory as “LHR mRNA binding protein (LRBP).” Both rat and human granulosa cells also express high levels of LRBP and the functional studies demonstrated that it interferes with the LHR expression in a manner similar to that seen in the luteinized ovary (32–34). The presence to MVK (LRBP) activity has been demonstrated in the interstitial cells of rat testis (35) but so far no functional studies have been carried out in LH responsive Leydig cells. Recent evidence suggests that in addition to gonadotropin, MVK/LRBP, a member of the oxysterol responsive gene family, is also regulated transcriptionally by the cholesterol responsive transcription factors, sterol regulatory element-binding protein-1a (SREBP-1a) and SREBP-2 (36). These various findings can be interpreted to suggest that ovarian steroid hormone biosynthesis, which is under LH regulation via LHR and is dependent on the cholesterol metabolism for the availability of cholesterol substrate, are integrated through a common regulatory mechanism acting at the level of LHR mRNA expression.