{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe steroidogenic acute regulatory (STAR) protein is indispensable for steroid hormone biosynthesis, as it mediates the rate‐limiting transport of cholesterol from the outer to the inner mitochondrial membrane. Structural and biophysical studies have revealed that STAR contains a hydrophobic cholesterol–binding pocket whose function relies on dynamic conformational transitions—including a pH–dependent molten globule state and a gating mechanism driven by its C–terminal alpha–helix. Mutations that perturb these structural features impair cholesterol binding and transport, thereby leading to severe endocrine disorders such as congenital lipoid adrenal hyperplasia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSTAR expression is subject to intricate regulation at transcriptional, post–transcriptional, and translational levels. In steroidogenic tissues, specific transcription factors—including LRH–1, FOXL2, AP–1, and C/EBP family members—along with hormonal stimuli mediated by protein kinase A, MAPK, and additional paracrine signals such as activins, BMP15, and leptin, finely tune STAR gene expression. Moreover, post–transcriptional modulators like TIS11B and noncoding RNAs (for example, let–7 and H19) further adjust STAR mRNA stability and translation, thereby ensuring that STAR activity is precisely matched to physiological demands."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in steroidogenesis, aberrant STAR expression has been linked to diverse pathophysiological conditions. Altered STAR function contributes not only to variations in adrenal steroid production and atypical presentations of congenital lipoid adrenal hyperplasia but also influences inflammatory responses in macrophages, liver injury in acetaminophen overdose, and even metabolic and neoplastic changes, such as those observed in hepatocellular carcinoma. These findings underscore the broad clinical impact of STAR dysregulation and reveal that its activity in cholesterol trafficking may intersect with multiple signaling pathways in both endocrine and non–endocrine tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Douglas M Stocco "}, {"type": "b", "children": [{"type": "t", "text": "Clinical disorders associated with abnormal cholesterol transport: mutations in the steroidogenic acute regulatory protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0303-7207(02)00048-5"}], "href": "https://doi.org/10.1016/s0303-7207(02"}, {"type": "t", "text": "00048-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12044915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12044915"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Robert C Tuckey, Madeleine J Headlam, Himangshu S Bose, et al. 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