The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36

Zhou, Bing; Jia, Lijing; Zhang, Zhijian; Xiang, Liping; Yuan, Youwen; Zheng, Peilin; Liu, Bin; Ren, Xiaopeng; Bian, Hua; Xie, Liwei; Li, Yao; Lu, Jieli; Zhang, Huijie; Lu, Yan

doi:10.1002/advs.202002273

Cited by 34 publications

(34 citation statements)

References 60 publications

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“…CD36 is one of the best characterized mediators that promote the transport of fatty acids into cells. Abundant studies have demonstrated that the expression of hepatic CD36 is increased during the development of NAFLD with the capability of promoting hepatic fatty acids uptake, thus resulting in the enhancement of hepatic steatosis (Steneberg et al, 2015;Zhou et al, 2020). Consistent with previous reports, our study has shown increased mRNA expression of hepatic ACC1 and CD36 in MCD-induced NASH mice.…”

Section: Discussionsupporting

confidence: 92%

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Ying

Yao

et al. 2021

Front. Pharmacol.

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Nonalcoholic steatohepatitis (NASH) has become one of the serious causes of chronic liver diseases, characterized by hepatic steatosis, hepatocellular injury, inflammation and fibrosis, and lack of efficient therapeutic agents. Palmitoylethanolamide (PEA) is an endogenous bioactive lipid with various pharmacological activities, including anti-inflammatory, analgesic, and neuroprotective effects. However, the effect of PEA on nonalcoholic steatohepatitis is still unknown. Our study aims to explore the potential protective role of PEA on NASH and to reveal the underlying mechanism. In this study, the C57BL/6 mice were used to establish the NASH model through methionine- and choline-deficient (MCD) diet feeding. Here, we found that PEA treatment significantly improved liver function, alleviated hepatic pathological changes, and attenuated the lipid accumulation and hepatic fibrosis in NASH mice induced by MCD diet feeding. Mechanistically, the anti-steatosis effect of PEA may be due to the suppressed expression of ACC1 and CD36, elevated expression of PPAR-α, and the phosphorylation levels of AMPK. In addition, hepatic oxidative stress was greatly inhibited in MCD-fed mice treated with PEA via enhancing the expression and activities of antioxidant enzymes, including GSH-px and SOD. Moreover, PEA exerted a clear anti-inflammatory effect though ameliorating the expression of inflammatory mediators and suppressing the NLRP3 inflammasome pathway activation. Furthermore, the impaired autophagy in MCD-induced mice was reactivated with PEA treatment. Taken together, our research suggested that PEA protects against NASH through the inhibition of inflammation and restoration of autophagy. Thus, PEA may represent an efficient therapeutic agent to treat NASH.

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Section: Discussionsupporting

confidence: 92%

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Ying

Yao

et al. 2021

Front. Pharmacol.

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“…Novel HNF4α, FOXA1, and CEBPα binding motifs were found to be enriched at the unique responsive regulatory elements in rhesus macaques, as well as motifs for other TFs such as JUN and NR2F6 (Fig. 2e) that have been shown to be essential for the regulation of metabolism in the liver [42,43]. At loci with partial sequence conservation, these novel TFs binding motifs can be the result of sequence mutations in TF recognition sequences driving the divergence of regulatory element response between species (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

Costello¹,

Shin²,

Trac³

et al. 2020

Preprint

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BACKGROUND: Regulatory innovation is central to the evolution of species. Different nutritional sources are one environmental pressure that can lead to selection for novel regulatory elements. Dietary composition changes, including exposure to "western" diets with excess fat and sugar content, can lead to transcriptional regulatory changes in the liver. In order to investigate how transcriptional regulatory changes in response to a high fat diet diverge across species, we profiled chromatin accessibility, histone modifications and the transcriptome in livers of rhesus macaques and mice fed high fat and normal diets. RESULTS: While the majority of elements exhibiting changes in chromatin accessibility in response to a high fat diet are enriched for similar transcription factors across species, the loci that change are mostly species specific. These unique responsive regulatory elements are largely derived from transposable elements and are enriched for liver-specific transcription factors, such as HNF4ɑ. Furthermore, the majority of genes that respond to a high fat diet in rhesus macaques do not have a shared response in mice and are proximal to regulatory elements that display changes in chromatin accessibility only in rhesus macaques. CONCLUSIONS: Our study demonstrates that most of the liver regulatory elements that exhibit changes in chromatin accessibility in response to a high fat diet do so in a species-specific manner. These findings illustrate how a similar environmental stimulus can drive a divergent chromatin and transcriptional responses in evolutionary distinct mammalian species.

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“…Furthermore, the observed NR2F6 upregulation in biopsies of patients with defined cancer entities [ 39 , 45 , 47 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 59 ] ( Figure 1 and Table 1 ) might thus implicate an upregulation also of lymphatic NR2F6. This, however, still needs to be evaluated for patient stratification purposes.…”

Section: Beyond Current Immune Checkpoint Therapiesmentioning

confidence: 98%

“…Remarkably, beside its role in immune cells, NR2F6 expression also appears important in tumor cells, correlating with a faster tumor growth and worse patient overall survival outcomes ( Table 1 ). Human studies firmly established an increased NR2F6 expression in various cancer types such as leukemia [ 41 , 56 ], colon carcinoma [ 39 ], cervical cancer [ 42 ], ovarian cancer [ 43 , 44 ], breast cancer [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], lung cancer [ 45 , 58 ] and hepatocellular cancer [ 38 ], suggesting that NR2F6 might be a prognostic marker. NR2F6 might directly regulate and elevate the survivability of cancerous colon cells via XIAP (X-Linked Inhibitor of Apoptosis) [ 39 ], whereas it supports proliferation and metastasis in hepatocellular carcinoma via TIP60 regulation [ 38 ], which is already known to promote mammary tumorigenesis [ 58 ], pleural mesothelioma malignancy [ 59 ] and prostate cancer [ 60 ] growth.…”

Section: Beyond Current Immune Checkpoint Therapiesmentioning

confidence: 99%

Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

Klepsch

Siegmund

Baier

2021

Cancers

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Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector CD4+ and CD8+ T cells. It is likely that future treatment options will combine surface receptor and intracellular protein targets. Utilizing germline gene ablation as well as CRISPR/Cas9-mediated acute gene mutagenesis, the nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) has been firmly characterized as such an intracellular immune checkpoint in effector T cells. Targeting this receptor appears to be a strategy for improving anti-tumor immunotherapy responses, especially in combination with CTLA-4 and PD-1. Current preclinical experimental knowledge firmly validates the immune checkpoint function of NR2F6 in murine tumor models, which provides a promising perspective for immunotherapy regimens in humans in the near future. While the clinical focus remains on the B7/CD28 family members, protein candidate targets such as NR2F6 are now being investigated in laboratories around the world and in R&D companies. Such an alternative therapeutic approach, if demonstrated to be successful, could supplement the existing therapeutic models and significantly increase response rates of cancer patients and/or expand the reach of immune therapy regimens to include a wider range of cancer entities. In this perspective review, the role of NR2F6 as an emerging and druggable target in immuno-oncology research will be discussed, with special emphasis on the unique potential of NR2F6 and its critical and non-redundant role in both immune and tumor cells.

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The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36

Cited by 34 publications

References 60 publications

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

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