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. 2024 Jul 3;262(2):e230385.
doi: 10.1530/JOE-23-0385. Print 2024 Aug 1.

Differential regulation of STARD1, STARD4 and STARD6 in the human ovary

Nawal A Yahya  1 , Steven R King  1   2 , Bo Shi  1 , Aisha Shaaban  1 , Nicole E Whitfield  1 , Chunmei Yan  1   3 , Richard J Kordus  1 , Gail F Whitman-Elia  1 , Holly A LaVoie  1
Affiliations

Differential regulation of STARD1, STARD4 and STARD6 in the human ovary

Nawal A Yahya et al. J Endocrinol. .

Abstract

Cells actively engaged in de novo steroidogenesis rely on an expansive intracellular network to efficiently transport cholesterol. The final link in the transport chain is STARD1, which transfers cholesterol to the enzyme complex that initiates steroidogenesis. However, the regulation of ovarian STARD1 is not fully characterized, and even less is known about the upstream cytosolic cholesterol transporters STARD4 and STARD6. Here, we identified both STARD4 and STARD6 mRNAs in the human ovary but only detected STARD4 protein since the primary STARD6 transcript turned out to be a splice variant. Corpora lutea contained the highest levels of STARD4 and STARD1 mRNA and STARD1 protein, while STARD4 protein was uniformly distributed across ovarian tissues. Cyclic AMP analog (8Br-cAMP) and phorbol ester (PMA) individually increased STARD1 and STARD4 mRNA along with STARD1 protein and its phosphoform in cultured primary human luteinized granulosa cells (hGCs). STARD6 transcripts and STARD4 protein were unresponsive to these stimuli. Combining lower doses of PMA and 8Br-cAMP blunted the 8Br-cAMP stimulation of STARD1 protein. Increasing cholesterol levels by blocking its conversion to steroid with aminoglutethimide or by adding LDL reduced the STARD4 mRNA response to stimuli. Sterol depletion reduced the STARD1 mRNA and protein response to PMA. These data support a possible role for STARD4, but not STARD6, in supplying cholesterol for steroidogenesis in the ovary. We demonstrate for the first time how cAMP, PMA and sterol pathways separately and in combination differentially regulate STARD4, STARD6 and STARD1 mRNA levels, as well as STARD1 and STARD4 protein in human primary ovarian cells.

Keywords: START domain; cholesterol; human; luteinized granulosa; progesterone.

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