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Suppression of steroidogenesis and activator protein-1 transcription factor activity in rat adrenals by vitamin E
Parveen Abidi1, Susan Leers-Sucheta, Salman Azhar
1Geriatric Research, Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Abstract:
Excessive oxidative stress and associated macromolecular damage are considered to be key features of aging, and appear to contribute to the age-related decline in steroid hormone production in adrenal and testicular Leydig cells. The current studies were initiated to examine the potential mechanism by which excessive oxidative stress during aging attenuates the functional expression of the oxidant-responsive transcription factor Activator protein-1. Chronic oxidative stress was induced in vivo by maintaining groups of rats on a diet deficient in vitamin E for 6 months. Plasma, liver, and adrenal tissues from vitamin E-deficient animals had negligible levels of this vitamin and showed high susceptibility to in vitro lipid peroxidation. Synthesis and secretion of corticosterone in response to corticotropin (ACTH), dibutyryl-cAMP, or 20alpha-hydroxycholesterol in vitro was significantly reduced in adrenocortical cells prepared cells from rats deficient in vitamin E. AP-1 DNA-binding activity was diminished approximately 55 % in adrenal extracts from vitamin E-deficient rats with no corresponding change in the binding activity of SP-1. The vitamin E deficiency-mediated loss of AP-1 activity was not due to an alteration in the dimeric composition of constituent proteins, but rather to a general down-regulation of steady-state levels of members of the Fos and Jun families of proteins. Interestingly, vitamin E deficiency also reduced the expression of the redox-regulated Ref-1 protein. Collectively these data demonstrate that chronic oxidative stress specifically down-regulates essential components of the AP-1 transcription factor complex, and suggest that aberrancies in AP-1 expression may adversely affect processes crucial for intracellular cholesterol transport and steroid hormone production.
Insights
Aging causes oxidative stress, reducing steroid hormone production by down-regulating the Activator protein-1 (AP-1) transcription factor. Vitamin E deficiency in rats demonstrated this link, impacting adrenal cell function.
Area of Science:
- Endocrinology
- Molecular Biology
- Aging Research
Background:
- Oxidative stress and macromolecular damage are hallmarks of aging.
- Age-related decline in steroid hormone production is linked to cellular dysfunction.
- The role of oxidant-responsive transcription factors in aging is not fully understood.
Purpose of the Study:
- To investigate how oxidative stress during aging affects the Activator protein-1 (AP-1) transcription factor.
- To elucidate the mechanism by which aging-induced oxidative stress impacts steroid hormone production.
Main Methods:
- Rats were maintained on a vitamin E-deficient diet for 6 months to induce chronic oxidative stress.
- Adrenocortical cells were used to assess corticosterone synthesis and secretion.
- AP-1 DNA-binding activity and protein levels (Fos, Jun, Ref-1) were measured in adrenal extracts.
Main Results:
- Vitamin E deficiency led to increased lipid peroxidation and reduced corticosterone production in response to various stimuli.
- AP-1 DNA-binding activity decreased by approximately 55% in vitamin E-deficient rats.
- Down-regulation of Fos, Jun, and Ref-1 protein levels was observed, without altering SP-1 binding activity.
Conclusions:
- Chronic oxidative stress specifically down-regulates key components of the AP-1 transcription factor complex.
- Impaired AP-1 expression may negatively affect intracellular cholesterol transport and steroid hormone production during aging.
- This study highlights the critical role of oxidative stress and AP-1 in age-related endocrine decline.
