Abstract
Hepatic lipogenesis is nutritionally regulated (i.e., downregulated during fasting and upregulated during the postprandial state) as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP-1c are known to be critical for nutritionally regulatedlipogenesis, upstream mechanisms governing Srebf1 expression remain unclear. Here, we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism and have therapeutic implications for the treatment of hyperlipidemia.
Highlights
Upon fasting, mRNA expression of the Srebf1 gene is markedly decreased, resulting in reduced amounts of SREBP-1c protein in liver nuclei, with corresponding decreases in the mRNAs for SREBP-1-activated target genes such as fatty acid synthase, a rate-limiting enzyme for lipogenesis (Horton et al, 1998)
The Kru€ppel-like family of transcription factors is a subclass of Cys2/His2 zinc-finger DNA-binding proteins, and Kru€ppel-like factor 15 (KLF15) is expressed in multiple tissues, including the liver, white and brown adipose tissue, kidney, heart, and skeletal muscle, with the strongest expression levels occurring in the liver and kidney (Gray et al, 2002)
Identification of nutritional regulatory element (NuRE) on the Srebf1c Promoter by In Vivo Ad-Luc Analyses mRNA expression of hepatic Srebf1 gene is tightly regulated by nutritional conditions
Summary
MRNA expression of the Srebf gene is markedly decreased, resulting in reduced amounts of SREBP-1c protein in liver nuclei, with corresponding decreases in the mRNAs for SREBP-1-activated target genes such as fatty acid synthase (gene name, Fasn), a rate-limiting enzyme for lipogenesis (Horton et al, 1998). We and other authors have shown that liver X receptor (LXR), a nuclear receptor family member, transcriptionally regulates the Srebf gene expression (Repa et al, 2000; Yoshikawa et al, 2001). The precise molecular mechanism by which LXR regulates Srebf gene expression under distinct nutritional conditions remains unclear. We show through a series of experiments involving a genome-wide screening for transcription factors that fastinginduced Kru€ppel-like factor 15 (KLF15) interacts with LXR to repress Srebf gene transcription as the primary mechanism of this nutritional regulation. The Kru€ppel-like family of transcription factors is a subclass of Cys2/His zinc-finger DNA-binding proteins, and KLF15 is expressed in multiple tissues, including the liver, white and brown adipose tissue, kidney, heart, and skeletal muscle, with the strongest expression levels occurring in the liver and kidney (Gray et al, 2002). The hepatic abundance of KLF15 is induced during the fasting state, and KLF15 is known to contribute to the regulation of gluconeogenesis in the liver (Gray et al, 2007; Teshigawara et al, 2005)
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