OVERVIEW

Insulin is critical for the regulation of systemic glucose homeostasis. Ectopic hepatic lipid accumulation and disordered fatty acid metabolism are critical for the pathogenesis of insulin resistance and hyperglycemic in obese states. A better understanding of the mechanisms of lipid and glucose metabolism will provide important insights for the prevention and therapeutic treatment for fatty liver disease and type 2 diabetes. Li laboratory is focused on the study of key metabolic regulators of signal transduction pathways in the key metabolic tissue of the liver.

THE APPROACHES

The research interest of Li laboratory is to study pathophysiological mechanisms of metabolic diseases. We are currently focused on identifying novel metabolic regulators of signal transduction pathways in metabolic tissues including liver and adipose tissue. We have a major research effort in the study of molecular mechanisms that regulate lipid, glucose and energy metabolism at the transcriptional and post-translational levels. We aim to dissect these biological processes by employing a variety of molecular and cellular approaches, and animal models including both genetically modified (transgenic and knockout) and diet-induced mouse models. The ultimate goal of this integrated approach is to unravel potential therapeutic targets of metabolic pathways for treating metabolic syndrome, such as fatty liver disease, hyperglycemia, hyperlipidemia, insulin resistance, type 2 diabetes and obesity.

李于实验室以研究糖尿病和脂肪肝等疾病的病理生理学机制为中心,通过筛查与细胞信号转导和代谢调控密切相关的蛋白因子, 利用分子生物学和细胞生物学等手段, 结合基因敲除或者饮食诱导的代谢疾病老鼠模型,研究相关蛋白因子生物学功能。重点研究基因转录调控以及翻译后修饰在调控脂质代谢、糖代谢和能量代谢过程中的作用, 从而阐明与肥胖相关的代谢性疾病的发病机制。

THE INNOVATIONS AND DISCOVERIES

1. Regulation of Insulin Resistance and Type 2 Diabetes

Recently, Li laboratory identified a novel mechanism for the HIF prolyl hydroxylase domain protein 3 (PHD3)-dependent proline hydroxylation of cAMP responsive element binding protein (CREB)-regulated transcriptional coactivator 2 (CRTC2) in the regulation of hepatic gluconeogenesis. Mechanistically, catalytic domain of PHD3 specifically binds to and directly hydroxylates the CREB coactivator CRTC2 at two amino acid residues proline 129 and 615 (Pro129 and Pro615), and hydroxylation of CRTC2 increases its association with CREB and nuclear translocation, which leads to enhanced transcription of gluconeogenic gene.

2. Regulation of Metabolism and Cell Growth by CREB/ATF bZIP transcription factor (CREBZF)

CREBZF has recently emerged as an important transcriptional coregulator involved in hepatic metabolism and cell growth. Recently, Li laboratory identified a novel mechanism for CREB/ATF bZIP transcription factor (CREBZF) in chronic inflammatory responses to potentiate insulin resistance and type 2 diabetes. Mechanistically, macrophage CREBZF promotes NF-κB signaling by competitively inhibiting the binding of IκBα to p65, which leads to enhanced transcription of proinflammatory genes. Additionally, researchers identified bromocriptine as a small molecule inhibitor of CREBZF in macrophages, which is sufficient to suppress diet-induced proinflammatory phenotypes and improve metabolic dysfunction.

PHD3-mediated noncanonical CRTC2 hydroxylation-dependent activation of hepatic gluconeogenesis

(Proceedings of the National Academy of Sciences. 2023, 120(23):e2219419120)

Li laboratory's recent work revealed that CREBZF deficiency in hepatocytes alleviated NASH phenotypes, including decreased hepatocyte injury, inflammation and fibrogenesis, in mice fed with AMLN diet. Moreover, hepatic overexpression of CREBZF in mice exacerbated NASH phenotypes.

Macrophage CREBZF in regulating adipose tissue inflammation and insulin resistance

(Advanced Science. 2024, e2306685)

Hepatic CREBZF as a checkpoint in regulating the progression of nonalcoholic steatohepatitis

(Hepatology. 2023, 78(5):1492-1505)

Recently, Li laboratory identified that CREBZF, a novel ATF/CREB family transcription cofactor, senses insulin signaling and stimulates expression of lipogenic genes. They demonstrate that CREBZF-dependent inhibition of Insig represent a molecular mechanism by which extracellular hormonal cues are transduced into the cell, and then regulate Insig-mediated feedback regulation of lipogenesis, which may contribute to hepatic steatosis, dyslipidemia and insulin resistance.

Li laboratory’s recent work showed that FGF21 improves hepatic insulin sensitivity by inhibiting mTORC1 in mice (Hepatology, 2016). The discovery demonstrates that liver is a direct target tissue of FGF21 actions, and mTORC1 inhibition mediates effects of FGF21 on improving hepatic insulin sensitivity. This work was highlighted by editorial article in Hepatology as “Fibroblast Growth Factor 21 Signaling: The Liver in Focus” (Hepatology, 2016), and was selected as one of the “10 breakthrough research in Hepatology in 2016” by MedSci.

Regulation of hepatic insulin sensitivity by FGF21-βKlotho-mediated inhibition of mTORC1 activation

(Hepatology. 2016, 64(2):425-438)

3. Regulation of NAFLD and NASH

The team, collaborating with Tasly Pharmaceutical Co. Ltd and Kunming Biomed International (KBI), compared in vitro bioactivity of B1344 and FGF21 on human- and monkey-derived receptor complex, and further demonstrated the therapeutic efficacies of B1344 in rodent and nonhuman primate models.

Transcriptional regulation of Insig and selective insulin resistance by CREBZF in the liver.

(Hepatology. 2018, 68(4):1361-1375)

The group also demonstrates that AMPK phosphorylates Insig and represses its ubiquitination and degradation via inhibiting the interaction between Insig and the ubiquitin ligase gp78, which prevents the proteolytic processing and activation of SREBP-1c. Moreover, the beneficial effects of metformin on hepatic steatosis are partially mediated by activation of Insig. This work was published online in Nature Communications.

Beneficial effects of B1344 on the progression of nonalcoholic fatty liver disease in obese cynomolgus monkeys

(Diabetes. 2020, 69(8):1611-1623)

Post-translational regulation of Insig by AMPK Phosphorylation

(Nature Communications. 2019, 10(1):623)