Inhibition of Estrogen-Related Receptor α Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis

Chen, Chien‐Yu; Li, Yang; Zeng, Ni; He, Liyun; Zhang, Xinwen; Tu, Taojian; Tang, Qi; Alba, Mario M.; Mir, Sabrina; Stiles, Eileen X.; Hong, Handan; Cadenas, Enrique; Stolz, Andrew; Li, Gang; Stiles, Bangyan L.

doi:10.1016/j.ajpath.2021.04.007

Cited by 16 publications

(10 citation statements)

References 62 publications

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“…Genetic or pharmacological inhibition of ERRα can reduce fat weight and lipid accumulation and resist high fat-diet-induced obesity ( 68 ). ERRα can also stimulate adipogenesis by increasing the accumulation of triglycerides ( 69 ). From a metabolic standpoint, lipid metabolism is significantly upregulated in EC, affecting the treatment outcome and/or disease progression of patients ( 70 ).…”

Section: Errα Participates In Regulated Glucose and Lipid Metabolism ...mentioning

confidence: 99%

Role of HIF-1α/ERRα in Enhancing Cancer Cell Metabolism and Promoting Resistance of Endometrial Cancer Cells to Pyroptosis

Mao

et al. 2022

Front. Oncol.

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Oxygen is critical to energy metabolism, and tumors are often characterized by a hypoxic microenvironment. Owing to the high metabolic energy demand of malignant tumor cells, their survival is promoted by metabolic reprogramming in the hypoxic microenvironment, which can confer tumor cell resistance to pyroptosis. Pyroptosis resistance can inhibit anti-tumor immunity and promote the development of malignant tumors. Hypoxia inducible factor-1α (HIF-1α) is a key regulator of metabolic reprogramming in tumor cells, and estrogen-related receptor α (ERRα) plays a key role in regulating cellular energy metabolism. Therefore, the close interaction between HIF-1α and ERRα influences the metabolic and functional changes in cancer cells. In this review, we summarize the reprogramming of tumor metabolism involving HIF-1α/ERRα. We review our understanding of the role of HIF-1α/ERRα in promoting tumor growth adaptation and pyroptosis resistance, emphasize its key role in energy homeostasis, and explore the regulation of HIF-1α/ERRα in preventing and/or treating endometrial carcinoma patients. This review provides a new perspective for the study of the molecular mechanisms of metabolic changes in tumor progression.

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Section: Errα Participates In Regulated Glucose and Lipid Metabolism ...mentioning

confidence: 99%

Role of HIF-1α/ERRα in Enhancing Cancer Cell Metabolism and Promoting Resistance of Endometrial Cancer Cells to Pyroptosis

Mao

et al. 2022

Front. Oncol.

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“…Consistently, plasmas from NASH patients were found to contain high levels of mitochondrial DNA and these mitochondrial DNA signal through TLR9 to regulate hepatic inflammation, acting as a potential mechanism for how steatosis establishes the proinflammatory tumor microenvironment. In addition, targeting mitochondrial functions attenuates steatosis and inflammation in the liver ( 196 , 197 ). Together, this evidence suggests that targeting steatosis via reducing lipid burden and/or altering mitochondrial function can impact liver cancer development.…”

Section: The Therapeutic Potential Of Targeting Steatosis For Liver C...mentioning

confidence: 99%

Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis

Alba

Datta

et al. 2022

Front. Oncol.

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Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.

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“…In addition, there are some other targets for NAFLD and NASH treatments, such as G protein-coupled receptors ( GPCRs ) [ 142 ], estrogen-related receptor alpha ( ERRα ) [ 143 ], bone morphogenetic proteins ( BMPs ) [ 144 ], and KLFs [ 24 , 145 ]. The treatment options for NAFLD/NASH are summarized in the graphic picture ( Figure 2 ).…”

Section: Treatment Options For Nafld and Nashmentioning

confidence: 99%

Current Options and Future Directions for NAFLD and NASH Treatment

Zhang

Yang

2021

IJMS

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, there is no currently approved treatment. NAFLD accounts as a major causing factor for the development of hepatocellular carcinoma (HCC), and its incidence rises accompanying the prevalence of obesity and diabetes. Reprogramming of antidiabetic and anti-obesity medicine is a major treatment option for NAFLD and NASH. Liver inflammation and cellular death, with or without fibrosis account for the progression of NAFLD to NASH. Therefore, molecules and signaling pathways involved in hepatic inflammation, fibrosis, and cell death are critically important targets for the therapy of NAFLD and NASH. In addition, the avoidance of aberrant infiltration of inflammatory cytokines by treating with CCR antagonists also provides a therapeutic option. Currently, there is an increasing number of pre-clinical and clinical trials undergoing to evaluate the effects of antidiabetic and anti-obesity drugs, antibiotics, pan-caspase inhibitors, CCR2/5 antagonists, and others on NAFLD, NASH, and liver fibrosis. Non-invasive serum diagnostic markers are developed for fulfilling the need of diagnostic testing in a large amount of NAFLD cases. Overall, a better understanding of the underlying mechanism of the pathogenesis of NAFLD is helpful to choose an optimized treatment.

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Inhibition of Estrogen-Related Receptor α Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis

Cited by 16 publications

References 62 publications

Role of HIF-1α/ERRα in Enhancing Cancer Cell Metabolism and Promoting Resistance of Endometrial Cancer Cells to Pyroptosis

Role of HIF-1α/ERRα in Enhancing Cancer Cell Metabolism and Promoting Resistance of Endometrial Cancer Cells to Pyroptosis

Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis

Current Options and Future Directions for NAFLD and NASH Treatment

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