The stearoyl-CoA desaturase 1 (SCD1) gene at 10q24.31 encodes the rate limiting enzyme SCD1 that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). Dysregulated SCD1 activity has been observed in many human diseases including non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, hyperlipidemia, metabolic syndrome and several types of cancer. HNF4A is a central regulator of glucose and lipid metabolism and previous studies suggested that it is deeply involved in regulating the SCD1 activity in the liver. However, the underlying mechanisms on whether and how SCD1 is regulated by HNF4A have not been explored in detail. In this study, we found that HNF4A regulates SCD1 expression by directly binding to the key regulatory regions in the SCD1 locus. Knocking down of HNF4A significantly downregulated the expression of SCD1. Variants rs55710213 and rs56334587 in intron 5 of SCD1 directly reside in a canonical HNF4A binding site. The GG haplotype of rs55710213 and rs56334587 is associated with decreased SCD1 activity by disrupting the binding of HNF4A, which further decreased the enhancer activity and SCD1 expression. In conclusion, our study demonstrated that SCD1 is directly regulated by HNF4A, which may be helpful in the understanding of the altered metabolic pathways in many diseases associated with dysregulated SCD1 or HNF4A or both.

位于 10q24.31的硬脂酰辅酶 A 去饱和酶 1 ( SCD1 ) 基因编码限速酶 SCD1，该酶催化饱和脂肪酸 (SFA) 生物合成单不饱和脂肪酸 (MUFA)。已在许多人类疾病中观察到 SCD1 活性失调，包括非酒精性脂肪肝 (NAFLD)、肥胖、高血压、高脂血症、代谢综合征和几种类型的癌症。HNF4A 是葡萄糖和脂质代谢的中枢调节剂，之前的研究表明它与肝脏中 SCD1 活性的调节密切相关。然而，关于SCD1是否以及如何受 HNF4A 调节的潜在机制尚未详细探讨。在这项研究中，我们发现 HNF4A 调节SCD1通过直接结合SCD1基因座中的关键调控区来表达。敲低HNF4A显着下调SCD1的表达。SCD1内含子 5 中的变体 rs55710213 和 rs56334587直接位于典型的 HNF4A 结合位点。rs55710213 和 rs56334587 的 GG 单倍型通过破坏 HNF4A 的结合而与 SCD1 活性降低有关，这进一步降低了增强子活性和SCD1表达。总之，我们的研究表明SCD1受 HNF4A 直接调节，这可能有助于理解与失调的SCD1或SCD1相关的许多疾病中改变的代谢途径。HNF4A或两者兼而有之。