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Development. 2019 Oct 17;146(20). pii: dev178335. doi: 10.1242/dev.178335.

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands.

Suzuki A1,2, Shim J1,2, Ogata K1,2, Yoshioka H1,2, Iwata J3,2,4.

Author information

1
Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA.
2
Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA.
3
Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA junichi.iwata@uth.tmc.edu.
4
MD Anderson Cancer Center University of Texas Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA.

Abstract

It has been long appreciated that sex hormone receptors are expressed in various non-gonadal organs. However, it remains unclear how sex hormones regulate the morphogenesis of these non-gonadal organs. To address this issue, we used a male mouse model of androgen-dependent salivary gland morphogenesis. Mice with excessive cholesterol synthesis in the salivary glands exhibited defects in the maturation of granular convoluted tubules (GCTs), which is regulated through sex hormone-dependent cascades. We found that excessive cholesterol synthesis resulted in autophagy failure specifically in the duct cells of salivary glands, followed by the accumulation of NRF2, a transcription factor known as one of the specific substrates for autophagy. The accumulated NRF2 suppressed the expression of Foxa1, which forms a transcriptional complex with the androgen receptor to regulate target genes. Taken together, our results indicate that cholesterol metabolism plays a crucial role in GCT differentiation through autophagy.

KEYWORDS:

Autophagy; Cholesterol metabolism; Differentiation; Duct formation; Salivary glands

PMID:
31558435
DOI:
10.1242/dev.178335

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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