1434 Epithelially derived MPZL3 negatively regulates murine and human sebaceous gland size and sebocyte proliferation

The sebaceous gland (SG) engages in holocrine secretion to produce lipid-rich sebum critical for skin homeostasis and various skin functions. SG undergoes continuous self-renewal to replenish differentiated sebocytes lost during holocrine secretion, as well as hair cycle-dependent oscillations in size, regulated by both skin epithelially derived signals as well as paracrine and systemic factors. We have previously demonstrated that Myelin Protein Zero-like 3 (MPZL3), a mitochondrially localized, nuclear encoded immunoglobulin-like v-type protein, regulates SG function. Mpzl3 global knockout mice show SG hypertrophy and sebocyte hyperplasia. In this study, we show that keratin 14 promoter-driven Cre-mediated epithelia-specific Mpzl3 knockout (epiKO) mice also develop SG hypertrophy and sebocyte hyperplasia, indicating that intraepithelial, mitochondrially localized MPZL3 negatively controls murine SG size and sebocyte proliferation. In human SG, MPZL3 mRNA expression is restricted to the junctional zone where sebocyte progenitors are localized, and the peripheral zone and proliferative zone, while MPZL3 protein is also detected in the maturation zone and degenerative zone, which could result from a much longer half-life of MPZL3 protein compared to transcripts. Moreover, MPZL3 knock-down in human SG organ culture significantly induces SG hyperplasia and increases (not significantly) PPARγ expression and the production of neutral lipids (measured by Oil Red O). Given that perturbed SG homeostasis and function are observed in many dermatoses such as acne vulgaris, atopic dermatitis, cicatricial alopecia, psoriasis, seborrheic dermatitis, and benign or malignant SG tumors, understanding MPZL3 regulation of SG homeostasis may have significant clinical implications.