Cholesterol Contributes to Male Sex Differentiation Through Its Developmental Role in Androgen Synthesis and Hedgehog Signaling

Kothandapani, Anbarasi; Jefcoate, Colin R.; Jorgensen, Joan S.

doi:10.1210/endocr/bqab066

Cited by 5 publications

(3 citation statements)

References 144 publications

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“…Our data are consistent with studies performed in experimental rodent and human liver disease (57)(58)(59), showing that injuryinduced release of Hedgehog ligands from epithelia leads to hepatic myofibroblast activation. Studies in other organs in humans, mice, zebrafish, and fruit flies also support the ability of Hedgehog signaling to drive local and remote tissue development, cancer, and post-injury fibrosis (60)(61)(62)(63)(64)(65). The literature on cardiac Hedgehog signaling has focused mainly on the beneficial impact of Hedgehog signaling in cardiac development and on successful scar formation in the first 7 days after myocardial infarction (66).…”

Section: Discussionmentioning

confidence: 95%

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis

et al. 2023

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Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1 + ) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 + cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1 + cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell–resolution transcriptomic analysis, we identified an “inflammatory” proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)–induced IHH production in vivo. TNF-induced Ubiquitin D ( Ubd ) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1 + cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8 -expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1 + cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

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Section: Discussionmentioning

confidence: 95%

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis

et al. 2023

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“…Epidemiological and preclinical observations have suggested that cholesterol-lowering plays a role in reducing the development and progression prostate cancer ( Alfaqih et al, 2017 ; Revilla et al, 2021 ). Cholesterol is an important precursor for de novo androgen synthesis ( Kothandapani et al, 2021 ). Similarly, androgen also plays a critical role in the pathogenesis and development of prostate cancer ( Dai et al, 2017 ).…”

Section: Anti-cancer Mechanisms Of Ezetimibementioning

confidence: 99%

Ezetimibe and Cancer: Is There a Connection?

Zhu

et al. 2022

Front. Pharmacol.

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The high level of serum cholesterol caused by the excessive absorption of cholesterol can lead to hypercholesteremia, thus promoting the occurrence and development of cancer. Ezetimibe is a drug that reduces cholesterol absorption and has been widely used for the treatment of patients with high circulating cholesterol levels for many years. Mechanistically, ezetimibe works by binding to NPC1L1, which is a key mediator of cholesterol absorption. Accumulating data from preclinical models have shown that ezetimibe alone could inhibit the development and progression of cancer through a variety of mechanisms, including anti-angiogenesis, stem cell suppression, anti-inflammation, immune enhancement and anti-proliferation. In the past decade, there has been heated discussion on whether ezetimibe combined with statins will increase the risk of cancer. At present, more and more evidence shows that ezetimibe does not increase the risk of cancers, which supports the role of ezetimibe in anti-cancer. In this review, we discussed the latest progress in the anti-cancer properties of ezetimibe and elucidated its underlying molecular mechanisms. Finally, we highlighted the potential of ezetimibe as a therapeutic agent in future cancer treatment and prevention.

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“…Androgens are first produced by the Leydig cells in the fetal testis, in which express the key steroidogenic enzymes for androgen production Cytochrome P450 17a1 ( Cyp17a1 ) and 3β-Hydroxysteroid (3β-HSD) ( 11 ). These two enzymes and other enzymes in the cascade of steroidogenesis convert cholesterol to androgens ( 11 , 12 ). The testis-derived androgens then enter the blood circulation and reach the target organs.…”

Section: Mechanisms Of Androgen Signaling Pathwaymentioning

confidence: 99%

One Tool for Many Jobs: Divergent and Conserved Actions of Androgen Signaling in Male Internal Reproductive Tract and External Genitalia

2022

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In the 1940s, Alfred Jost demonstrated the necessity of testicular secretions, particularly androgens, for male internal and external genitalia differentiation. Since then, our knowledge of androgen impacts on differentiation of the male internal (Wolffian duct) and external genitalia (penis) has been drastically expanded upon. Between these two morphologically and functionally distinct organs, divergent signals facilitate the establishment of tissue-specific identities. Conversely, conserved actions of androgen signaling are present in both tissues and are largely responsible for the growth and expansion of the organs. In this review we synthesize the existing knowledge of the cell type-specific, organ specific, and conserved signaling mechanisms of androgens. Mechanistic studies on androgen signaling in the Wolffian duct and male external genitalia have largely been conducted in mouse model organisms. Therefore, the majority of the review is focused on mouse model studies.

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Cholesterol Contributes to Male Sex Differentiation Through Its Developmental Role in Androgen Synthesis and Hedgehog Signaling

Cited by 5 publications

References 144 publications

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis

Ezetimibe and Cancer: Is There a Connection?

One Tool for Many Jobs: Divergent and Conserved Actions of Androgen Signaling in Male Internal Reproductive Tract and External Genitalia

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