Hepatocyte TIPE2 is a fasting-induced Raf-1 inactivator that drives hepatic gluconeogenesis to maintain glucose homeostasis

Yan Tao; Jingyuan Zhao; Jilong Yin; Zixin Zhou; Huijie Li; Jinhao Zang; Tianci Wang; Yalin Wang; Chun Guo; Faliang Zhu; Shen Dai; Fuwu Wang; Hui Zhao; Haiting Mao; Fengming Liu; Lining Zhang; Qun Wang

doi:10.1016/j.metabol.2023.155690

Hepatocyte TIPE2 is a fasting-induced Raf-1 inactivator that drives hepatic gluconeogenesis to maintain glucose homeostasis

Metabolism. 2023 Nov:148:155690. doi: 10.1016/j.metabol.2023.155690. Epub 2023 Sep 16.

Authors

Yan Tao¹, Jingyuan Zhao¹, Jilong Yin¹, Zixin Zhou¹, Huijie Li¹, Jinhao Zang¹, Tianci Wang¹, Yalin Wang¹, Chun Guo¹, Faliang Zhu¹, Shen Dai², Fuwu Wang³, Hui Zhao⁴, Haiting Mao⁴, Fengming Liu¹, Lining Zhang¹, Qun Wang⁵

Affiliations

¹ Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
² Department of Physiology and Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
³ Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Mental Disorders, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
⁴ Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
⁵ Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address: wangqun@sdu.edu.cn.

PMID: 37717724
DOI: 10.1016/j.metabol.2023.155690

Abstract

Background: The liver regulates metabolic balance during fasting-feeding cycle. Hepatic adaptation to fasting is precisely modulated on multiple levels. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a negative regulator of immunity that reduces several liver pathologies, but its physiological roles in hepatic metabolism are largely unknown.

Methods: TIPE2 expression was examined in mouse liver during fasting-feeding cycle. TIPE2-knockout mice, liver-specific TIPE2-knockout mice, liver-specific TIPE2-overexpressed mice were examined for fasting blood glucose and pyruvate tolerance test. Primary hepatocytes or liver tissues from these mice were evaluated for glucose production, lipid accumulation, gene expression and regulatory pathways. TIPE2 interaction with Raf-1 and TIPE2 transcription regulated by PPAR-α were examined using gene overexpression or knockdown, co-immunoprecipitation, western blot, luciferase reporter assay and DNA-protein binding assay.

Results: TIPE2 expression was upregulated in fasted mouse liver and starved hepatocytes, which was positively correlated with gluconeogenic genes. Liver-specific TIPE2 deficiency impaired blood glucose homeostasis and gluconeogenic capacity in mice upon fasting, while liver-specific TIPE2 overexpression elevated fasting blood glucose and hepatic gluconeogenesis in mice. In primary hepatocytes upon starvation, TIPE2 interacted with Raf-1 to accelerate its ubiquitination and degradation, resulting in ERK deactivation and FOXO1 maintenance to sustain gluconeogenesis. During prolonged fasting, hepatic TIPE2 deficiency caused aberrant activation of ERK-mTORC1 axis that increased hepatic lipid accumulation via lipogenesis. In hepatocytes upon starvation, PPAR-α bound with TIPE2 promoter and triggered its transcriptional expression.

Conclusions: Hepatocyte TIPE2 is a PPAR-α-induced Raf-1 inactivator that sustains hepatic gluconeogenesis and prevents excessive hepatic lipid accumulation, playing beneficial roles in hepatocyte adaptation to fasting.

Keywords: Fasting; Gluconeogenesis; Glucose; Hepatocyte; TIPE2.