Functional loss of inactive rhomboid-like protein 2 mitigates obesity by suppressing pro-inflammatory macrophage activation-triggered adipose inflammation

Xu, Minxuan; Ge, Changrong; Qin, Yuting; Lou, Deshuai; Li, Qiang; Feng, Jing; Wu, Yekuan; Hu, Linfeng; Wang, Bochu; Tan, Jun

doi:10.1016/j.molmet.2020.01.008

Cited by 12 publications

(12 citation statements)

References 39 publications

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“…iRhom2 plays a crucial role in the maturation and transport of TACE and the hydrolysis of the extracellular hydrolysis of TNF-α [16,17]. iRhom2 genedeficient mice exhibit reduced levels of TNF-α [18][19][20][21][22]. Our previous study indicated that 4-HIL inhibited inflammation in HepG2 cells and 3 T3-L1 adipocytes by decreasing TACE and TNF-α [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

“…Earlier studies demonstrated that iRhom2 mediated the maturation and transport of TACE in macrophages by directly binding to TACE, and thus mediated the extracellular hydrolysis of TNF-α [16,17]. iRhom2 gene-deficient mice exhibit reduced the levels of TNF-α [18][19][20][21][22]. Thus, iRhom2 might be a promising therapeutic target in the development of novel anti-diabetes and anti-obesity treatment.…”

Section: Introductionmentioning

confidence: 99%

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4-Hydroxyisoleucine relieves inflammation through iRhom2-dependent pathway in co-cultured macrophages and adipocytes with LPS stimulation

Zhou

Chen

Gao

et al. 2020

BMC Complement Med Ther

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Background 4-Hydroxyisoleucine (4-HIL) is an active ingredient extracted from Trigonella foenum-graecum L., a Chinese traditional herbal medicine, which exerts the efficacy of anti-obesity and anti-diabetes. We previously reported that 4-HIL potentiates anti-inflammatory and anti-insulin resistance effects through down-regulation of TNF-α and TNF-α converting enzyme (TACE) in 3 T3-L1 adipocytes and HepG2 cells. In the present study, we further investigate the effects and mechanisms of 4-HIL on obesity-induced inflammation in RAW264.7 macrophages and 3 T3-L1 adipocytes co-culture system. Methods RAW264.7 macrophages and 3 T3-L1 adipocytes were co-cultured to mimic the microenvironment of adipose tissue. siRNA-iRhom2 transfection was performed to knockdown iRhom2 expression in RAW264.2 macrophages. The mRNA and protein expression of iRhom2 and TACE were measured by real-time quantitative PCR (RT-qPCR) and western blotting. The production of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), IL-6 and IL-10 were evaluated by ELISA. The ratio of M2/M1 was detected by flow cytometry. Results 4-HIL significantly repressed the mRNA and protein levels of iRhom2 and TACE in RAW264.7 macrophages after LPS stimulated. Meanwhile, the levels of pro-inflammatory cytokines, including TNF-α, MCP-1, and IL-6, were substantially suppressed by 4-HIL in the co-culture system. Moreover, the level of anti-inflammatory cytokine IL-10 was increased significantly by 4-HIL in the co-culture system after LPS stimulation. Additionally, the ratio of M2/M1 was also increased by 4-HIL in the co-culture system after LPS stimulation. Finally, these effects of 4-HIL were largely enhanced by siRNA-iRhom2 transfection. Conclusion Taken together, our results indicated that obesity-induced inflammation was potently relieved by 4-HIL, most likely through the iRhom2-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

4-Hydroxyisoleucine relieves inflammation through iRhom2-dependent pathway in co-cultured macrophages and adipocytes with LPS stimulation

Zhou

Chen

Gao

et al. 2020

BMC Complement Med Ther

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“…Mice lacking iRhom2 are protected from the metabolic complications associated with obesity, including weight gain, dyslipidemia, and insulin resistance, when challenged by a high‐fat diet (HFD) [73,87]. They burn excess fat more efficiently than WT controls, by increasing thermogenesis in brown adipose tissue (BAT) and by promoting white adipose tissue beiging, a phenomenon whereby so‐called brown beige adipocytes which have a higher thermogenic potential by virtue of their expression of the key thermogenic gene, UCP‐1 (uncoupling protein‐1), are recruited within white adipose tissues.…”

Section: Physiological Roles Of Rhomboid Pseudoproteasesmentioning

confidence: 99%

The complex life of rhomboid pseudoproteases

Adrain

Cavadas

2020

The FEBS Journal

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Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily. The founding members, rhomboids, were first identified in Drosophila as serine intramembrane proteases that cleave transmembrane proteins, enabling signaling. This led to the discovery of the wider rhomboid superfamily, a clan that in metazoans is dominated by pseudoproteases. These so-called rhomboid pseudoproteases inherited from their catalytically active ancestors a conserved rhomboid-like domain and a propensity to regulate signaling. Lacking catalytic activity, they developed new 'pseudoenzyme' functions that include regulating the trafficking, turnover, and activity of their client proteins. Rhomboid pseudoproteases have preeminent roles in orchestrating immune cell activation, antiviral responses, and cytokine release in response to microbial infection, or in chronic diseases, and have also been implicated in growth factor signaling, cancer, and, more recently, metabolism. Here, we discuss the mechanism(s) of action of rhomboid pseudoproteases, contrasted with rhomboid proteases. We also highlight the roles of rhomboid pseudoproteases in mammalian physiology, which, quite paradoxically among pseudoenzymes, is understood much better than active rhomboids.

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“…Interestingly, recent studies using an independently generated line of iRhom2-deficient mice, came to different conclusions regarding the role of iRhom2 in diet-induced obesity and metabolic complications of HFD (84,85). In particular, Badenes et al (84) have reported that loss of iRhom2 protects mice from weight gain, chronic inflammation in adipose tissues, hepatic steatosis and insulin resistance when challenged by a high-calorie diet.…”

Section: The Role Of Irhom2 In Obesity-induced Low-grade Inflammationmentioning

confidence: 99%

The Role of iRhom2 in Metabolic and Cardiovascular-Related Disorders

Geesala

Issuree

Maretzky

2020

Front. Cardiovasc. Med.

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Chronic obesity is associated with metabolic imbalance leading to diabetes, dyslipidemia, and cardiovascular diseases (CVDs), in which inflammation is caused by exposure to inflammatory stimuli, such as accumulating sphingolipid ceramides or intracellular stress. This inflammatory response is likely to be prolonged by the effects of dietary and blood cholesterol, thereby leading to chronic low-grade inflammation and endothelial dysfunction. Elevated levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF) are predictive of CVDs and have been widely studied for potential therapeutic strategies. The release of TNF is controlled by a disintegrin and metalloprotease (ADAM) 17 and both are positively associated with CVDs. ADAM17 also cleaves most of the ligands of the epidermal growth factor receptor (EGFR) which have been associated with hypertension, atherogenesis, vascular dysfunction, and cardiac remodeling. The inactive rhomboid protein 2 (iRhom2) regulates the ADAM17-dependent shedding of TNF in immune cells. In addition, iRhom2 also regulates the ADAM17-mediated cleavage of EGFR ligands such as amphiregulin and heparin-binding EGF-like growth factor. Targeting iRhom2 has recently become a possible alternative therapeutic strategy in chronic inflammatory diseases such as lupus nephritis and rheumatoid arthritis. However, what role this intriguing interacting partner of ADAM17 plays in the vasculature and how it functions in the pathologies of obesity and associated CVDs, are exciting questions that are only beginning to be elucidated. In this review, we discuss the role of iRhom2 in cardiovascular-related pathologies such as atherogenesis and obesity by providing an evaluation of known iRhom2-dependent cellular and inflammatory pathways.

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Functional loss of inactive rhomboid-like protein 2 mitigates obesity by suppressing pro-inflammatory macrophage activation-triggered adipose inflammation

Cited by 12 publications

References 39 publications

4-Hydroxyisoleucine relieves inflammation through iRhom2-dependent pathway in co-cultured macrophages and adipocytes with LPS stimulation

4-Hydroxyisoleucine relieves inflammation through iRhom2-dependent pathway in co-cultured macrophages and adipocytes with LPS stimulation

The complex life of rhomboid pseudoproteases

The Role of iRhom2 in Metabolic and Cardiovascular-Related Disorders

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