Coordination between the circadian clock and androgen signaling is required to sustain rhythmic expression of Elovl3 in mouse liver

Abstract

Edited by Qi-Qun Tang ELOVL3 is a very long-chain fatty acid elongase, and its mRNA levels display diurnal rhythmic changes exclusively in adult male mouse livers. This cyclical expression of hepatic Elovl3 is potentially controlled by the circadian clock, related hormones, and transcriptional factors. It remains unknown, however, whether the circadian clock, in conjunction with androgen signaling, functions in maintaining the rhythmic expression of Elovl3 in a sexually dimorphic manner. Under either zeitgeber or circadian time, WT mouse livers exhibited a robust circadian rhythmicity in the expression of circadian clock genes and Elovl3. In contrast, male Bmal1 ؊/؊ mice displayed severely weakened expression of hepatic circadian clock genes, resulting in relatively high, but nonrhythmic, Elovl3 expression levels. ChIP assays revealed that NR1D1 binds to the Elovl3 promoter upon circadian change in WT mouse livers in vivo, and a diminished binding was observed in male Bmal1 ؊/؊ mouse livers. Additionally, female mouse livers exhibited constant low levels of Elovl3 expression. Castration markedly reduced Elovl3 expression levels in male mouse livers but did not disrupt circadian variation of Elovl3. Injection of female mice with 5␣-dihydrotestosterone induced Elovl3 rhythmicity in the liver. In AML12 cells, 5␣-dihydrotestosterone also elevated Elovl3 expression in a time-dependent manner. In contrast, flutamide efficiently attenuated this induction effect. In conclusion, a lack of either the circadian clock or androgen sig-naling impairs hepatic Elovl3 expression, highlighting the observation that coordination between the circadian clock and androgen signaling is required to sustain the rhythmic expression of Elovl3 in mouse liver. Elovl3 (elongation of very long-chain fatty acids 3), also known as Cig30, was initially identified as a thermogenesisrelated gene after its expression in brown adipose tissue was found to be highly elevated in response to cold stimulation (1). Accumulating reports indicate that significant Elovl3 expression also occurs in white adipose tissue, liver, and triglyceriderich glands, such as the sebaceous and meibomian glands (2-5). As a member of the Elovl gene family, Elovl3 encodes an enzyme that functions in the synthesis of C20-C24 saturated and mono-unsaturated very long-chain fatty acids (VLCFAs). 5 It was previously demonstrated that Elovl3 Ϫ/Ϫ mice exhibit a clear skin phenotype with an impaired barrier function resulting from changes in the synthesis of C20-C24 saturated and mono-unsaturated VLCFAs, triglyceride synthesis, and sebum formation (5). Male Elovl3 Ϫ/Ϫ mice also display a diminished capacity to accumulate fat within brown adipose tissue (6). Additionally, male and female Elovl3 Ϫ/Ϫ mice possess reduced hepatic lipogenic gene expression and triglyceride content and are also resistant to diet-induced obesity (7). These findings indicate that ELOVL3 acts as an important regulator of triglyceride and lipid droplet formation in skin, adipose tissue, and liver. To further det...

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