Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment

Zhang, Peng; Chen, Zhimin; Kuang, Henry; Liu, Tongyu; Zhu, Jiaqiang; Zhou, Linkang; Wang, Qiuyu; Xiong, Xuelian; Meng, Ziyi; Qiu, Xing‐Biao; Jacks, Ramiah D.; Liu, Lu; Li, Siming; Lumeng, Carey N.; Li, Qing; Zhou, Xiang; Lin, Jiandie D.

doi:10.1016/j.cmet.2022.07.010

Cited by 52 publications

(53 citation statements)

References 78 publications

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“…(Jaitin et al, 2019;Hendrikx et al, 2022) Furthermore, a large body of evidence demonstrated that TREM2 + macrophages have an anti-inflammatory role. (Jaitin et al, 2019;Remmerie et al, 2020;Zhang et al, 2022;Zhou et al, 2022) Conversely, Ramachandran et al described scar-associated macrophages in human cirrhotic liver that co-expressed LAM signature genes, such as TREM2, GPNMB, CD9 and SSP1, but also mitogens for fibroblasts such as PDGFB and TNSFS12 (TWEAK) and displayed a pro-fibrotic phenotype. (Ramachandran et al, 2019) TREM2 is a transmembrane receptor of the immunoglobulin superfamily that recognizes lipids and apolipoproteins, and promotes immune tolerance during NAFLD.…”

Section: Liver Macrophage Roles In the Installment Of Liver Steatosismentioning

confidence: 99%

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

Kohlhepp

Liu

Tacke

et al. 2023

Front. Mol. Biosci.

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Chronic liver diseases from varying etiologies generally lead to liver fibrosis and cirrhosis. Among them, non-alcoholic fatty liver disease (NAFLD) affects roughly one-quarter of the world population, thus representing a major and increasing public health burden. Chronic hepatocyte injury, inflammation (non-alcoholic steatohepatitis, NASH) and liver fibrosis are recognized soils for primary liver cancer, particularly hepatocellular carcinoma (HCC), being the third most common cause for cancer-related deaths worldwide. Despite recent advances in liver disease understanding, therapeutic options on pre-malignant and malignant stages remain limited. Thus, there is an urgent need to identify targetable liver disease-driving mechanisms for the development of novel therapeutics. Monocytes and macrophages comprise a central, yet versatile component of the inflammatory response, fueling chronic liver disease initiation and progression. Recent proteomic and transcriptomic studies performed at singular cell levels revealed a previously overlooked diversity of macrophage subpopulations and functions. Indeed, liver macrophages that encompass liver resident macrophages (also named Kupffer cells) and monocyte-derived macrophages, can acquire a variety of phenotypes depending on microenvironmental cues, and thus exert manifold and sometimes contradictory functions. Those functions range from modulating and exacerbating tissue inflammation to promoting and exaggerating tissue repair mechanisms (i.e., parenchymal regeneration, cancer cell proliferation, angiogenesis, fibrosis). Due to these central functions, liver macrophages represent an attractive target for the treatment of liver diseases. In this review, we discuss the multifaceted and contrary roles of macrophages in chronic liver diseases, with a particular focus on NAFLD/NASH and HCC. Moreover, we discuss potential therapeutic approaches targeting liver macrophages.

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Section: Liver Macrophage Roles In the Installment Of Liver Steatosismentioning

confidence: 99%

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

Kohlhepp

Liu

Tacke

et al. 2023

Front. Mol. Biosci.

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“…Neuregulin 4 (NRG4) is an adipose tissue-derived endocrine factor that has been demonstrated to suppress NASH-associated HCC by restraining the tumor-prone liver immune microenvironment. A recombinant fusion protein comprising amino acids 1–55 of human NRG4 and the Fc domain of immunoglobulin G 1 was found to suppress HCC induced by a NASH diet plus oncogene overexpression[ 125 ].…”

Section: Potential Targets Outside the Livermentioning

confidence: 99%

Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

Wang¹,

Zhang²,

Guan³

2023

World J Gastroenterol

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Nonalcoholic fatty liver disease (NAFLD), a leading chronic disease worldwide, affects approximately a quarter of the global population. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD and is more likely to progress to liver fibrosis than simple steatosis. NASH is also identified as the most rapidly growing cause of hepatocellular carcinoma. Although in the past decade, several phase II/III clinical trials have shown promising results in the use of novel drugs targeting lipid synthase, farnesoid X receptor signaling, peroxisome proliferator-activated receptor signaling, hepatocellular injury, and inflammatory signaling, proven pharmaceutical agents to treat NASH are still lacking. Thus, continuous exploration of the mechanism underlying the pathogenesis of NAFLD and the identification of novel therapeutic targets remain urgent tasks in the field. In the current review, we summarize studies reported in recent years that not only provide new insights into the mechanisms of NAFLD development but also explore the possibility of treating NAFLD by targeting newly identified signaling pathways. We also discuss evidence focusing on the intrahepatic targets involved in the pathogenesis of NAFLD as well as extrahepatic targets affecting liver metabolism and function.

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Section: Introductionmentioning

confidence: 99%

“…A recent study by Zhang et al ( Zhang et al, 2022b ) demonstrated that the Nrg4 endocrine axis can arrest the development of HCC by inhibiting the tumor-promoting microenvironment in NASH. It was demonstrated that there was a strong induction of tumor-like macrophages and exhaustion of CD8 + T cells (cytotoxic T lymphocytes) in NASH, and Nrg4 knockout mice were shown to exacerbate the deregulation of the hepatic immune microenvironment ( Zhang et al, 2022b ). Further construction of human Nrg4-Fc fusion protein revealed remarkably reduced induction of NASH-associated macrophages and T-cell depletion-related gene expression in the liver, demonstrating its potent inhibitory effect on the tumor-prone microenvironment in mice ( Zhang et al, 2022b ).…”

Section: Introductionmentioning

confidence: 99%

“…It was demonstrated that there was a strong induction of tumor-like macrophages and exhaustion of CD8 + T cells (cytotoxic T lymphocytes) in NASH, and Nrg4 knockout mice were shown to exacerbate the deregulation of the hepatic immune microenvironment ( Zhang et al, 2022b ). Further construction of human Nrg4-Fc fusion protein revealed remarkably reduced induction of NASH-associated macrophages and T-cell depletion-related gene expression in the liver, demonstrating its potent inhibitory effect on the tumor-prone microenvironment in mice ( Zhang et al, 2022b ). Together, these solid findings demonstrate that Nrg4 serves as an immune checkpoint involved in the crosstalk of the pro-oncogenic microenvironment in NASH and can protect against HCC through profound immune reprogramming ( Figure 4 ).…”

Section: Introductionmentioning

confidence: 99%

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Neuregulin 4 as a novel adipokine in energy metabolism

Liu

Chen

2023

Front. Physiol.

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Adipose tissue has been shown to play a key role in energy metabolism and it has been shown to regulate metabolic homeostasis through the secretion of adipokines. Neuregulin 4 (Nrg4), a novel adipokine secreted mainly by brown adipose tissue (BAT), has recently been characterized as having an important effect on the regulation of energy homeostasis and glucolipid metabolism. Nrg4 can modulate BAT-related thermogenesis by increasing sympathetic innervation of adipose tissue and therefore has potential metabolic benefits. Nrg4 improves metabolic dysregulation in various metabolic diseases such as insulin resistance, obesity, non-alcoholic fatty liver disease, and diabetes through several mechanisms such as anti-inflammation, autophagy regulation, pro-angiogenesis, and lipid metabolism normalization. However, inconsistent findings are found regarding the effects of Nrg4 on metabolic diseases in clinical settings, and this heterogeneity needs to be further clarified by future studies. The potential metabolic protective effect of Nrg4 suggests that it may be a promising endocrine therapeutic target.

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Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment

Cited by 52 publications

References 78 publications

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

Neuregulin 4 as a novel adipokine in energy metabolism

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