Dataset Information

KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting.

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 regulated lipogenesis, 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.

SUBMITTER: Takeuchi Y

PROVIDER: S-EPMC5031553 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting.

Takeuchi Yoshinori Y Yahagi Naoya N Aita Yuichi Y Murayama Yuki Y Sawada Yoshikazu Y Piao Xiaoying X Toya Naoki N Oya Yukari Y Shikama Akito A Takarada Ayako A Masuda Yukari Y Nishi Makiko M Kubota Midori M Izumida Yoshihiko Y Yamamoto Takashi T Sekiya Motohiro M Matsuzaka Takashi T Nakagawa Yoshimi Y Urayama Osamu O Kawakami Yasushi Y Iizuka Yoko Y Gotoda Takanari T Itaka Keiji K Kataoka Kazunori K Nagai Ryozo R Kadowaki Takashi T Yamada Nobuhiro N Lu Yuan Y Jain Mukesh K MK Shimano Hitoshi H

Cell reports 20160818 9

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 regulated lipogenesis, upstream mechanisms governing Srebf1 expression remain unclear. Here, we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a c ...[more]

PMID: 27545894

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Project description:During early fasting, increases in skeletal muscle proteolysis liberate free amino acids for hepatic gluconeogenesis in response to pancreatic glucagon. Hepatic glucose output diminishes during the late protein-sparing phase of fasting, when ketone body production by the liver supplies compensatory fuel for glucose-dependent tissues. Glucagon stimulates the gluconeogenic program by triggering the dephosphorylation and nuclear translocation of the CREB regulated transcription coactivator 2 (CRTC2; also known as TORC2), while parallel decreases in insulin signalling augment gluconeogenic gene expression through the dephosphorylation and nuclear shuttling of forkhead box O1 (FOXO1). Here we show that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin 1 (SIRT1), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which we show here is also activated by dephosphorylation at Ser 89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at Lys 628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the Sirt1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha, encoded by Ppargc1a) by SIRT1 activators, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.

Dataset Information

KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting.

Publications

KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting.

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