Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a ubiquitin E3 ligase that regulates important biological processes. However, the role of TRAF6 in cardiac hypertrophy remains unknown. ...Here, we show that TRAF6 levels are increased in human and murine hypertrophied hearts, which is regulated by reactive oxygen species (ROS) production. Cardiac-specific Traf6 overexpression exacerbates cardiac hypertrophy in response to pressure overload or angiotensin II (Ang II) challenge, whereas Traf6 deficiency causes an alleviated hypertrophic phenotype in mice. Mechanistically, we show that ROS, generated during hypertrophic progression, triggers TRAF6 auto-ubiquitination that facilitates recruitment of TAB2 and its binding to transforming growth factor beta-activated kinase 1 (TAK1), which, in turn, enables the direct TRAF6-TAK1 interaction and promotes TAK1 ubiquitination. The binding of TRAF6 to TAK1 and the induction of TAK1 ubiquitination and activation are indispensable for TRAF6-regulated cardiac remodelling. Taken together, we define TRAF6 as an essential molecular switch leading to cardiac hypertrophy in a TAK1-dependent manner.
Background and Aims
NAFLD is the most prevalent chronic liver disease worldwide, but no effective pharmacological therapeutics are available for clinical use. NASH is the more severe stage of NAFLD. ...During this progress, dysregulation of endoplasmic reticulum (ER)–related pathways and proteins is one of the predominant hallmarks. We aimed to reveal the role of ring finger protein 5 (RNF5), an ER‐localized E3 ubiquitin‐protein ligase, in NASH and to explore its underlying mechanism.
Approach and Results
We first inspected the expression level of RNF5 and found that it was markedly decreased in livers with NASH in multiple species including humans. We then introduced adenoviruses for Rnf5 overexpression or knockdown into primary mouse hepatocytes and found that palmitic acid/oleic acid (PAOA)–induced lipid accumulation and inflammation in hepatocytes were markedly attenuated by Rnf5 overexpression but exacerbated by Rnf5 gene silencing. Hepatocyte‐specific Rnf5 knockout significantly exacerbated hepatic steatosis, inflammatory response, and fibrosis in mice challenged with diet‐induced NASH. Mechanistically, we identified 3‐hydroxy‐3‐methylglutaryl CoA reductase degradation protein 1 (HRD1) as a binding partner of RNF5 by systematic interactomics analysis. RNF5 directly bound to HRD1 and promoted its lysine 48 (K48)–linked and K33‐linked ubiquitination and subsequent proteasomal degradation. Furthermore, Hrd1 overexpression significantly exacerbated PAOA‐induced lipid accumulation and inflammation, and short hairpin RNA–mediated Hrd1 knockdown exerted the opposite effects. Notably, Hrd1 knockdown significantly diminished PAOA‐induced lipid deposition, and up‐regulation of related genes resulted from Rnf5 ablation in hepatocytes.
Conclusions
These data indicate that RNF5 inhibits NASH progression by targeting HRD1 in the ubiquitin‐mediated proteasomal pathway. Targeting the RNF5–HRD1 axis may provide insights into the pathogenesis of NASH and pave the way for developing strategies for NASH prevention and treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse ...effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib’s benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP–activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug’s current use in HCC.
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•Low-dose sorafenib safely suppresses NASH progression in mice•Low-dose sorafenib resolves NASH in monkeys without detectable toxicities•AMPK activation is required for the therapeutic effects of sorafenib in NASH•Sorafenib activates AMPK by acting as a mitochondrial uncoupler
Jian et al. show that low-dose sorafenib safely and effectively suppressed NASH progression in both mice and monkeys. Mechanistically, induction of mitochondrial uncoupling and subsequent AMPK activation primarily underlies the therapeutic effects of sorafenib in NASH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Global distributions and trends of the risk-attributable burdens of chronic obstructive pulmonary disease (COPD) have rarely been systematically explored. To guide the formulation of targeted and ...accurate strategies for the management of COPD, we analyzed COPD burdens attributable to known risk factors.
Using detailed COPD data from the Global Burden of Disease study 2019, we analyzed disability-adjusted life years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), and deaths attributable to each risk factor from 1990 to 2019. Additionally, we calculated estimated annual percentage changes (EAPCs) during the study period. The population attributable fraction (PAF) and summary exposure value (SEV) of each risk factor are also presented.
From 1990 to 2019, the age-standardized DALY and death rates of COPD attributable to smoking and household air pollution, occupational particles, secondhand smoke, and low temperature presented consistently declining trends in almost all socio-demographic index (SDI) regions. However, the decline in YLD was not as dramatic as that of the death rate. In contrast, the COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure showed undesirable increasing trends in the low- and low-middle-SDI regions. In addition, the age-standardized DALY and death rates attributable to each risk factor except household air pollution and low temperature were the highest in the low-middle-SDI region. In 2019, the COPD burden attributable to smoking ambient particulate matter, ozone, occupational particles, low and high temperature was obviously greater in males than in females. Meanwhile, the most important risk factors for female varied across regions (low- and low-middle-SDI regions: household air pollution; middle-SDI region: ambient particles; high-middle- and high-SDI region: smoking).
Increasing trends of COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure in the low-middle- and low-SDI regions call for an urgent need to implement specific and effective measures. Moreover, considering the gender differences in COPD burdens attributable to some risk factors such as ambient particulate matter and ozone with similar SEV, further research on biological differences between sexes in COPD and relevant policy-making of disease prevention are required.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. ...Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.
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•12,862 COVID-19 cases on corticosteroid therapy or not were retrospectively studied•NLR at admission is a key factor for patients with high or low risk of death•An NLR > 6.11 was associated with lower mortality in patients on corticosteroids•Corticosteroids did not reduce mortality in patients with an NLR ≤ 6.11 or with T2D
While corticosteroid therapy is effective in the treatment of patients with severe COVID-19, a quantitative clinical parameter to identify such severity and which patients would respond well to corticosteroids has not been developed. Here, Cai et al. find that a simple blood test that measures the neutrophil-to-leukocyte ratio at admission discriminates high versus low mortality risk and a better response to corticosteroid therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inhibition of apoptosis signal‐regulating kinase 1 (ASK1) activation has emerged as a promising target for the treatment of nonalcoholic steatohepatitis (NASH). Multiple forms of posttranslational ...modifications determine the activity of ASK1. In addition to phosphorylation, recent studies revealed that ubiquitination is essential for ASK1 activation. However, the endogenous factor that regulates ASK1 ubiquitination and activation remains poorly defined. In this study, we identified the E3 ligase Skp1‐Cul1‐F‐box (SCF) protein F‐box/WD repeat‐containing protein 5 (FBXW5) as a key endogenous activator of ASK1 ubiquitination. FBXW5 is the central component of the SCF complex (SCFFbxw5) that directly interacts with and ubiquitinates ASK1 in hepatocytes during NASH development. An in vivo study showed that hepatocyte‐specific overexpression of FBXW5 exacerbated diet‐induced systemic and hepatic metabolic disorders, as well as the activation of ASK1‐related mitogen‐activated protein kinase (MAPK) signaling in the liver. Conversely, hepatocyte‐specific deletion of FBXW5 significantly prevented the progression of these abnormalities. Mechanically, FBXW5 facilitated the addition of Lys63‐linked ubiquitin to ASK1 and thus exacerbated ASK1‐c‐Jun N‐terminal kinase/p38 MAPK signaling, inflammation, and lipid accumulation. Furthermore, we demonstrated that the N‐terminus (S1) and C‐terminus (S3) of FBXW5 respectively and competitively ablate the function of FBXW5 on ASK1 activation and served as effective inhibitors of NASH progression. Conclusion: This evidence strongly suggests that SCFFbxw5 is an important activator of ASK1 ubiquitination in the context of NASH. The development of FBXW5(S1) or FBXW5(S3)‐mimicking drugs and screening of small‐molecular inhibitors specifically abrogating ASK1 ubiquitination‐dependent activation are viable approaches for NASH treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Aims
NAFLD has become the most common liver disease worldwide but lacks a well‐established pharmacological therapy. Here, we aimed to investigate the role of an E3 ligase SH3 ...domain‐containing ring finger 2 (SH3RF2) in NAFLD and to further explore the underlying mechanisms.
Methods and Results
In this study, we found that SH3RF2 was suppressed in the setting of NAFLD across mice, monkeys, and clinical individuals. Based on a genetic interruption model, we further demonstrated that hepatocyte SH3RF2 deficiency markedly deteriorates lipid accumulation in cultured hepatocytes and diet‐induced NAFLD mice. Mechanistically, SH3RF2 directly binds to ATP citrate lyase, the primary enzyme promoting cytosolic acetyl–coenzyme A production, and promotes its K48‐linked ubiquitination‐dependent degradation. Consistently, acetyl–coenzyme A was significantly accumulated in Sh3rf2‐knockout hepatocytes and livers compared with wild‐type controls, leading to enhanced de novo lipogenesis, cholesterol production, and resultant lipid deposition.
Conclusion
SH3RF2 depletion in hepatocytes is a critical aggravator for NAFLD progression and therefore represents a promising therapeutic target for related liver diseases.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological ...treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.
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IJS, NUK, SBMB, UL, UM, UPUK
Background and Aims
Although the prevalence of NAFLD has risen dramatically to 25% of the adult population worldwide, there are as yet no approved pharmacological interventions for the disease ...because of uncertainty about the underlying molecular mechanisms. It is known that mitochondrial dysfunction is an important factor in the development of NAFLD. Mitochondrial antiviral signaling protein (MAVS) is a critical signaling adaptor for host defenses against viral infection. However, the role of MAVS in mitochondrial metabolism during NAFLD progression remains largely unknown.
Approach and Results
Based on expression analysis, we identified a marked down‐regulation of MAVS in hepatocytes during NAFLD progression. By using MAVS global knockout and hepatocyte‐specific MAVS knockout mice, we found that MAVS is protective against diet‐induced NAFLD. MAVS deficiency induces extensive mitochondrial dysfunction during NAFLD pathogenesis, which was confirmed as impaired mitochondrial respiratory capacity and membrane potential. Metabolomics data also showed the extensive metabolic disorders after MAVS deletion. Mechanistically, MAVS interacts with the N‐terminal stretch of voltage‐dependent anion channel 2 (VDAC2), which is required for the ability of MAVS to influence mitochondrial function and hepatic steatosis.
Conclusions
In hepatocytes, MAVS plays an important role in protecting against NAFLD by helping to regulate healthy mitochondrial function. These findings provide insights regarding the metabolic importance of conventional immune regulators and support the possibility that targeting MAVS may represent an avenue for treating NAFLD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Aims
Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decades, the internal restrictive mechanisms remain ...largely unknown. We have recently reported that the transcription repressor interferon regulatory factor‐2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically down‐regulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown.
Approach and Results
Herein, using gain‐of‐function and loss‐of‐function approaches in mice, we demonstrated that while hepatocyte‐specific Irf2bp2 knockout exacerbated high‐fat diet–induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout‐exaggerated hepatosteatosis in vitro.
Conclusion
IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance, and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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