Multifaceted landscape of the StAR protein in steroid biosynthesis: from development to degeneration

Regulation of steroid hormone biosynthesis is principally mediated by the steroidogenic acute regulatory (StAR) protein and involves endocrine, autocrine, and paracrine signaling in a variety of classical and non-classical tissues. Cholesterol is the precursor of all steroid hormones. The StAR protein, by mobilizing the transport of intra-mitochondrial cholesterol, regulates the biosynthesis of steroid hormones, which play pivotal roles in diverse physiological processes. Steroid biosynthesis is primarily mediated by mechanisms that enhance transcription, translation, or activation of StAR. These processes are primarily regulated by the cAMP/protein kinase A (PKA) pathway, in which a plethora of signaling plays permissible roles. Whereas gain-of-function of StAR, involving phosphorylation and/or acetylation, enhances the activity of StAR in optimal steroid biosynthesis, its loss-of-function, connecting mutations, markedly decreases the biosynthesis of steroid hormones. Deterioration in the steroidogenic machinery, including hormonal imbalance, modulates immunosenescence and results in the development of various health complications and diseases. Recent advances provide evidence that aberrant expression of StAR-driven estrogen, especially 17β-estradiol (E2), biosynthesis promotes breast tumorigenesis, in which StAR is uncovered as a novel acetylated protein. Moreover, age-associated progressive suppression of StAR-governed sex neurosteroids influences the most prevalent neurological disorder, Alzheimer’s disease, in both women and men. This review summarizes significant findings and the current understanding of the regulation of StAR in a variety of steroid-coupled events, ranging from organogenesis to carcinogenesis to neurodegeneration, and helps unravel the mechanistic insights into relevant physiological and pathophysiological implications.