Liver X receptor α promotes the synthesis of monounsaturated fatty acids in goat mammary epithelial cells via the control of stearoyl-coenzyme A desaturase 1 in an SREBP-1-dependent manner

Abstract

Stearoyl-coenzyme A desaturase 1 (SCD1) is a pivotal enzyme in the biosynthesis of monounsaturated fatty acids (MUFA). It is tightly regulated by transcription factors that control lipogenesis. In nonruminants, liver X receptor α (LXRα) is a nuclear receptor and transcription factor that acts as a key sensor of cholesterol and lipid homeostasis. However, the mechanism whereby LXRα regulates the expression and transcriptional activity of SCD1 in ruminant mammary cells remains unknown. In this study with goat mammary epithelial cells (GMEC), the LXRα agonist T 4506585 (T09) markedly enhanced the mRNA expression of SCD1 and sterol regulatory element binding factor 1 (SREBF1). The concentrations of C16:1 and C18:1 and their desaturation indices also were increased by LXRα activation. However, knockdown of LXRα did not alter the mRNA expression of SCD1. Although SCD1 was repressed by SREBF1 knockdown, T09 significantly increased SCD1 expression. Further analysis revealed that the SCD1 promoter activity was activated by LXRα overexpression. The goat SCD1 promoter contains 2 LXR response elements (LXRE), 1 sterol response element (SRE), and 1 nuclear factor Y (NF-Y) binding site. Site-directed mutagenesis of LXRE1, LXRE2, or SRE alone did not eliminate the upregulation of SCD1 when LXRα was overexpressed. In contrast, when NF-Y alone or in combination with SRE was mutated simultaneously, the basal transcriptional activity of the SCD1 promoter was markedly decreased and did not respond to LXRα overexpression. Furthermore, when SREBF1 was knocked down, overexpression of LXRα did not affect the promoter activity of SCD1. Together, these data suggest that LXRα regulates the expression of SCD1 through increasing SREBP-1 abundance to promote interaction with SRE and NF-Y binding sites. The present study provides evidence that LXRα is involved in the synthesis of MUFA in the goat mammary gland through an indirect mechanism.

Activation of liver X receptor promotes fatty acid synthesis in goat mammary epithelial cells via modulation of SREBP1 expression

“…Similar to the above findings, the activation of LXR directly increased the expression of lipogenic genes in bovine mammary epithelial cells in an SREBP1-independent fashion (Oppi-Williams et al, 2013). Several studies demonstrated a direct effect of LXR on the expression of SREBF1 and the downstream genes FASN and SCD1 in goat mammary cells (Li et al, 2015b;Yao et al, 2016). More recent is the demonstration that the LXRβ also control the expression of SREBP1c and FASN in goat mammary cells (Shi et al, 2017).…”

“…The role of LXR in controlling milk fat synthesis was initially demonstrated by work conducted in bovine mammary cells in vitro, where activation of LXRα by the specific agonist T0901317 increased the expression of SREBP1 and augmented de novo fatty acid synthesis (McFadden and Corl, 2010). Since then, much work has been done to clarify the transcriptional regulation mechanism of LXR on SREBP1 and the consequence on milk fat synthesis in ruminants (Wang et al, 2012;Oppi-Williams et al, 2013;Li et al, 2015b;Yao et al, 2016;Shi et al, 2017). However, much work remains to be done to determine whether the activation of LXR affects the network of genes involved in milk fat synthesis (Bionaz and Loor, 2008).…”

Relationships between serum total bilirubin levels and hypercholesterolemia in Chinese men and women.

“…In diabetes mellitus type I Sprague-Dawley rats models [29], serum TC and both serum and hepatic TG were decreased by TB. In the meanwhile, this effect accompanied by suppression of oxidative stress, as well as liver X receptor-α and Sterol regulatory element binding protein-1 which involved in regulating lipid synthesis and metabolism [30]. Secondly, insulin resistance could in uence their relationship.…”

Cadmium transcriptionally regulates Scd1 expression in silver pomfret

“…Sterol regulatory element binding transcription factor 1 (Srebp1) and liver X receptor α (Lxrα) play central roles in the transcriptional regulation of lipogenesis . In mammals, Srebp1 transactivates the scd1 promoter through sterol response elements (SREs) and nuclear factor (NF‐Y) binding sites . Lxrα indirectly promotes scd1 expression by increasing Srebp1 abundance .…”

“…In mammals, Srebp1 transactivates the scd1 promoter through sterol response elements (SREs) and nuclear factor (NF‐Y) binding sites . Lxrα indirectly promotes scd1 expression by increasing Srebp1 abundance . In addition to Srebp1 and Lxrα, the peroxisome proliferator–activated receptor γ (Pparγ) is also required for lipid synthesis .…”