Tissue-specific ablation of ACSL4 results in disturbed steroidogenesis

Authors: WANG, WEI - Stanford University; HAO, XIAO - Stanford University; HAN, LINA - Stanford University; YAN, ZHE - Stanford University; SHEN, WEN-JUN - Stanford University; DONG, DACHUAN - Stanford University; HASBARGEN, KATHRIN - Stanford University; BITTNER, STEFANIE - Va Palo Alto Health Care System (VAPAHCS); CORTEZ, JUAN - Stanford University; GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; AZHAR, SALMA - Stanford University; KRAEMER, FREDERC - Stanford University

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/21/2019
Publication Date: 8/27/2019
Citation: Wang, W., Hao, X., Han, L., Yan, Z., Shen, W., Dong, D., Hasbargen, K., Bittner, S., Cortez, J., Greenberg, A.S., Azhar, S., Kraemer, F.B. 2019. Tissue-specific ablation of ACSL4 results in disturbed steroidogenesis. Endocrinology. 160(11):2517-2528. https://doi.org/10.1210/en.2019-00464.
DOI: https://doi.org/10.1210/en.2019-00464

Interpretive Summary: We investigated whether the protein acyl CoA synthetase 4 (ACSL4), which is expressed in testes, is necessary for the production of testosterone and in the adrenal is necessary for the production of corticosterone. Our studies used a mouse which did not express ACSL4 in the testes and the adrenal and demonstrated that deficiency of ACSL4 in these organs resulted in reduced levels of corticosterone and testosterone. Since the production of corticosterone and testosterone falls as we age and reduced levels of these hormones detrimentally affect healthy aging, understanding how different nutrients regulate ACSL4 expression will be useful in designing strategies to help sustain healthy aging.

Technical Abstract: ACSL4 is a member of the ACSL family that catalyzes the conversion of long-chain fatty acids to acyl-coenzyme As, which are essential for fatty-acid incorporation and utilization in diverse metabolic pathways, including cholesteryl ester synthesis. Steroidogenic tissues such as the adrenal gland are particularly enriched in cholesteryl esters of long-chain polyunsaturated fatty acids, which constitute an important pool supplying cholesterol for steroid synthesis. The current studies addressed whether ACSL4 is required for normal steroidogenesis. CYP11A1 promoter-mediated Cre was used to generate steroid tissue-specific ACSL4 knockout (KO) mice. Results demonstrated that ACSL4 plays an important role in adrenal cholesteryl ester formation, as well as in determining the fatty acyl composition of adrenal cholesteryl esters, with ACSL4 deficiency leading to reductions in cholesteryl ester storage and alterations in cholesteryl ester composition. Statistically significant reductions in corticosterone and testosterone production, but not progesterone production, were observed in vivo, and these deficits were accentuated in ex vivo and in vitro studies of isolated steroid tissues and cells from ACSL4-deficient mice. However, these effects on steroid production appear to be due to reductions in cholesteryl ester stores rather than disturbances in signaling pathways. We conclude that ACSL4 is dispensable for normal steroidogenesis.