Novel insights into the ACTH- induced and basal steroidogenesis in adrenocortical cells
| dc.contributor.author | Sidhu, Simarjit | |
| dc.contributor.examiningcommittee | Shiu, Robert (Physiology and Pathophysiology) | en_US |
| dc.contributor.examiningcommittee | Xie, Jiuyong (Physiology and Pathophysiology) | en_US |
| dc.contributor.supervisor | Mishra, Suresh | |
| dc.date.accessioned | 2022-08-29T14:06:22Z | |
| dc.date.available | 2022-08-29T14:06:22Z | |
| dc.date.copyright | 2022-08-25 | |
| dc.date.issued | 2022-08-24 | |
| dc.date.submitted | 2022-08-26T00:22:51Z | en_US |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| dc.description.abstract | Adrenocortical cells — the corticosteroids-producing cells of the adrenal glands — are rich in cholesterol containing lipid droplets (LDs) and mitochondria, and both are steroidogenically interconnected. The former serves as the precursor substrate for corticosteroids biosynthesis whereas the later represents the site where corticosteroidogenesis begins. The corticosteroidogenesis has been studied extensively; however, a number of fundamental questions related to adrenocorticotrophic hormone (ACTH)-induced and basal steroidogenesis remain unclear, including cholesterol transport to the inner mitochondrial membrane (IMM) where steroidogenesis initiates and the role of intracellular cholesterol pool. Prohibitin-1 (PHB1) is an evolutionarily conserved protein that localizes to the IMM, where it functions as a lipid and protein chaperone. Recently, our laboratory has discovered that PHB1 plays a role in testicular Leydig cell steroidogenesis, involving cholesterol homeostasis and mitochondrial biology pertaining testosterone production. Thus, the present study investigates the role of PHB1 in corticosteroidogenesis (in vitro using human HAC15 and mouse Y-1 cell culture models), as the fundamental aspects of steroidogenesis related to cholesterol handling and mitochondrial biology are similar in different steroidogenic cell types. Manipulation of PHB1 level was found to affects mitochondria, lysosomes and lipid droplets characteristics, as well as corticoid production by adrenocortical cells. Mechanistically, I found that PHB1 modulates PKA and ERK signaling in adrenocortical cells. A consistent finding of PHB1’s role in steroidogenesis in adrenocortical cells from two different species, as well as previously in testosterone producing murine Leydig cells imply that its role in steroidogenesis is likely conserved. Moreover, as the framework of corticosteroidogenesis is built around cholesterol — the precursor substrate for steroid hormones, including its cellular uptake by adrenocortical cells, mobilization and trafficking to the IMM, I explored a potential role of intracellular cholesterol pool in corticosteroidogenesis in vitro using a simple approach that appears to be not exploited before. Cholesterol deprivation induced steroidogenic events/factors (as determined by their marker proteins) and increased basal steroidogenesis in adrenocortical cells. Data obtained suggest that cholesterol plays an important role in basal steroidogenesis. In summary, my findings provide new insights into ACTH-induced and basal steroidogenesis in adrenocortical cells. | en_US |
| dc.description.note | October 2022 | en_US |
| dc.description.sponsorship | 1. Natural Sciences and Engineering Research Council of Canada- https://doi.org/10.13039/501100000038. Grant Title- Illuminating the relationship between prohibition and sex steroid hormones in adipocyte biology, Grant number- RGPIN04962-17 2. Canadian Institutes of Health Research- https://doi.org/10.13039/501100000024- Grant title- Establishing essential research tools to advance the knowledge of interrelated sex differences in adipose and immune functions in health and disease. Grant number- PJX-175420 3. University of Manitoba Graduate Fellowship (UMGF)- U of M: https://doi.org/10.13039/100010318 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/36795 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Adrenal gland | en_US |
| dc.subject | Steroidogenesis | en_US |
| dc.subject | Mitochondria | en_US |
| dc.subject | Cholesterol | en_US |
| dc.subject | Autophagy | en_US |
| dc.title | Novel insights into the ACTH- induced and basal steroidogenesis in adrenocortical cells | en_US |
| dc.type | master thesis | en_US |
| local.subject.manitoba | no | en_US |
| oaire.awardNumber | PJT- 173394 | en_US |
| oaire.awardTitle | Exploring the role of a mitochondrial protein prohibition in leydig cell steroidogenesis | en_US |
| project.funder.identifier | https://doi.org/10.13039/501100000024 | en_US |
| project.funder.name | Canadian Institutes of Health Research | en_US |