FOXA3 induction under endoplasmic reticulum stress contributes to non-alcoholic fatty liver disease

Liu, Caizhi; Zhou, Bing; Meng, Meiyao; Zhao, Wenjun; Wang, Dongmei; Yuan, Youwen; Zheng, Ying; Qiu, Jin; Yu, Longquan; Li, Guoqiang; Xiong, Xuelian; Bian, Hua; Zhang, Huijie; Wang, Hua; Ma, Xinran; Hu, Cheng; Xu, Lingyan; Lu, Yan

doi:10.1016/j.jhep.2021.01.042

Cited by 61 publications

(36 citation statements)

References 42 publications

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“…Elevated levels of FOXA3 and SREBP-1c in the liver were found in both obese mice and NAFLD patients. This study confirmed that FOXA3 links stress to NAFLD progression, demonstrating the importance of the FOXA3/SREBP-1c transcriptional axis in NAFLD progression, proposing that FOXA3 is a potential therapeutic target for FLD [ 66 ]. However, there have been few studies on the relationship between mTOR and endoplasmic reticulum stress in NAFLD.…”

Section: Mtor Regulates Os Through Pig3 P53 Jnksupporting

confidence: 68%

mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

Feng

Qiu

Zhou

et al. 2022

IJMS

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The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the “multiple strikes” theory, the classic “two strikes” theory has not been overturned. Therefore, there is a crucial need to identify multiple targets in NAFLD pathogenesis for the development of diagnostic markers and targeted therapeutics. Since its discovery, the mechanistic target of rapamycin (mTOR) has been recognized as the central node of a network that regulates cell growth and development and is closely related to liver lipid metabolism and other processes. This paper will explore the mechanisms by which mTOR regulates lipid metabolism (SREBPs), insulin resistance (Foxo1, Lipin1), oxidative stress (PIG3, p53, JNK), intestinal microbiota (TLRs), autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD. The specific influence of mTOR on NAFLD was hypothesized to be divided into micro regulation (the mechanism of mTOR’s influence on NAFLD factors) and macro mediation (the relationship between various influencing factors) to summarize the influence of mTOR on the developmental process of NAFLD, and prove the importance of mTOR as an influencing factor of NAFLD regarding multiple aspects. The effects of crosstalk between mTOR and its upstream regulators, Notch, Hedgehog, and Hippo, on the occurrence and development of NAFLD-associated hepatocellular carcinoma are also summarized. This analysis will hopefully support the development of diagnostic markers and new therapeutic targets in NAFLD.

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Section: Mtor Regulates Os Through Pig3 P53 Jnksupporting

confidence: 68%

mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

Feng

Qiu

Zhou

et al. 2022

IJMS

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“…So far, ER has been regarded as a key regulator of systemic metabolic balance. Excessive nutrition, inflammation, and other metabolic diseases all result in the normal function of the ER being impaired, as well as the activation of three classical pathways of the UPR response [ 44 , 45 ]. The role of ER in the regulation of metabolism in hepatocytes and β cells has been well studied, but knowledge of the molecular mechanisms in adipocytes are still inadequate.…”

Section: Discussionmentioning

confidence: 99%

Collagen XV Promotes ER Stress-Induced Inflammation through Activating Integrin β1/FAK Signaling Pathway and M1 Macrophage Polarization in Adipose Tissue

Liu

et al. 2021

IJMS

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Collagen XV (Col XV), a basement membrane (BM) component, is highly expressed in adipose tissue, and studies have found that Col XV is related to extracellular matrix (ECM) remodeling involving in adipose tissue fibrosis and inflammation. Furthermore, the ECM is essential for maintaining normal development and tissue function. In this study, we found that Col XV is related to the endoplasmic reticulum stress (ERS) and inflammation of adipose tissue. Moreover, we found that overexpression of Col XV in mice could cause macrophages to infiltrate white adipose tissue (iWAT). At the same time, the expression of the ERS sensor IRE1α (Inositol-Requiring Enzyme-1α) was significantly up-regulated, which intensified the inflammation of adipose tissue and the polarization of M1 macrophages after the overexpression of Col XV in mice. In addition, after overexpression of Col XV, the intracellular Ca2+ concentration was significantly increased. Using focal adhesion kinase (FAK) inhibitor PF573228, we found that PF-573228 inhibited the phosphorylation of FAK and reversed the upward trend of Col XV-induced protein expression levels of IRE1α, C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). After treatment with IRE1α inhibitor STF-083010, the results showed that the expression of adipocyte inflammation-related genes interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) significantly were decreased. Our results demonstrate that Col XV induces ER-stress in adipocytes by activating the Integrinβ1/FAK pathway and disrupting the intracellular Ca2+ balance. At the same time, Col XV regulates the inflammation induced by ER stress in adipocytes by promoting IRE1α/XBP1 (X-Box binding protein 1) signaling. Our study provides new ideas for solving the problems of adipose tissue metabolism disorders caused by abnormal accumulation of ECM.

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“…An experimental study showed that only the transcriptional factor XBP1c under ERS interfered with the modulation of FOXA3 activity and led to lipid synthesis while FOXA3 inhibition reversed the lesions and improved ER activity even under HFD diets. No changes were found regarding the link between FOXA and inflammation, but experimental inhibition of FOXA3 reduced the inflammation [ 89 ]. Another element associated with ERS is autophagy, with its subtype, lipophagy, with a well-established role in energy homeostasis and hepatocyte lipid content, leading to NAFLD.…”

Section: Triggers Of Liver Inflammationmentioning

confidence: 99%

Chronic Inflammation—A Link between Nonalcoholic Fatty Liver Disease (NAFLD) and Dysfunctional Adipose Tissue

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is a new challenge in modern medicine, due to its high prevalence in the world. The pathogenesis of NAFLD is a complex dysmetabolic process, following the “multiple-hit” hypothesis that involves hepatocytes excessive accumulation of triglycerides, insulin resistance (IR), increased oxidative stress, chronic low-grade inflammatory response and lipotoxicity. In this review, we provide an overview of the interrelation of these processes, the link between systemic and local inflammation and the role of dysfunctional adipose tissue (AT) in the NAFLD development. Multiple extrahepatic triggers of the pathophysiological mechanisms of NAFLD are described: nutritional deficiency or malnutrition, unhealthy food intake, the dysfunction of the liver–gut axis, the involvement of the mesenteric adipose tissue, the role of adipokines such as adiponectin, of food intake hormone, the leptin and leptin resistance (LR) and adipose tissue’s hormone, the resistin. In addition, a wide range of intrahepatic players are involved: oxidative stress, fatty acid oxidation, endoplasmic reticulum stress, mitochondrial dysfunction, resident macrophages (Kupffer cells), neutrophils, dendritic cells (DCs), B and T lymphocytes contributing to the potential evolution of NAFLD to nonalcoholic steatohepatitis (NASH). This interdependent approach to complex dysmetabolic imbalance in NAFLD, integrating relevant studies, could contribute to a better clarification of pathogenesis and consequently the development of new personalized treatments, targeting de novo lipogenesis, chronic inflammation and fibrosis. Further studies are needed to focus not only on treatment, but also on prevention strategy in NAFLD.

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FOXA3 induction under endoplasmic reticulum stress contributes to non-alcoholic fatty liver disease

Cited by 61 publications

References 42 publications

mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

Collagen XV Promotes ER Stress-Induced Inflammation through Activating Integrin β1/FAK Signaling Pathway and M1 Macrophage Polarization in Adipose Tissue

Chronic Inflammation—A Link between Nonalcoholic Fatty Liver Disease (NAFLD) and Dysfunctional Adipose Tissue

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