Mitigation of non-alcoholic steatohepatitis via recombinant Orosomucoid 2, an acute phase protein modulating the Erk1/2-PPARγ-Cd36 pathway

Li, Li; Sun, Haoming; Chen, Jionghao; Ding, Cong; Yang, Xiaojun; Han, Hua; Sun, Qingzhu

doi:10.1016/j.celrep.2023.112697

Cited by 6 publications

(3 citation statements)

References 43 publications

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“…9 H; p = 0.0085). ORM2 protein secretion primarily emanated from hepatocytes 36 , 37 . Past investigations have delineated the role of ORM2 in neuroinflammation and ischemic stroke events 38 , 39 .…”

Section: Resultsmentioning

confidence: 99%

“…Among these, the ORM2, a liver-produced hepatokine, plays a crucial role in maintaining hepatic and systemic lipid balance and is implicated in regulating de novo lipogenesis 71 . ORM2 levels are associated with MASLD, while studies suggest its potential as a therapeutic target for liver diseases, particularly those related to lipid metabolism and steatohepatitis 36 . Additionally, ORM2 has shown promise as a biomarker for liver diseases, contributing to diagnostics and monitoring, emphasizing its significance in liver health and potential for therapeutic interventions 72 .…”

Section: Discussionmentioning

confidence: 99%

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Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach

Roy,

Saha,

Bose

et al. 2024

Sci Rep

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Heat stress exposure in intermittent heat waves and subsequent exposure during war theaters pose a clinical challenge that can lead to multi-organ dysfunction and long-term complications in the elderly. Using an aged mouse model and high-throughput sequencing, this study investigated the molecular dynamics of the liver-brain connection during heat stress exposure. Distinctive gene expression patterns induced by periodic heat stress emerged in both brain and liver tissues. An altered transcriptome profile showed heat stress-induced altered acute phase response pathways, causing neural, hepatic, and systemic inflammation and impaired synaptic plasticity. Results also demonstrated that proinflammatory molecules such as S100B, IL-17, IL-33, and neurological disease signaling pathways were upregulated, while protective pathways like aryl hydrocarbon receptor signaling were downregulated. In parallel, Rantes, IRF7, NOD1/2, TREM1, and hepatic injury signaling pathways were upregulated. Furthermore, current research identified Orosomucoid 2 (ORM2) in the liver as one of the mediators of the liver-brain axis due to heat exposure. In conclusion, the transcriptome profiling in elderly heat-stressed mice revealed a coordinated network of liver-brain axis pathways with increased hepatic ORM2 secretion, possibly due to gut inflammation and dysbiosis. The above secretion of ORM2 may impact the brain through a leaky blood–brain barrier, thus emphasizing intricate multi-organ crosstalk.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach

Roy,

Saha,

Bose

et al. 2024

Sci Rep

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show abstract

“…It is a secreted protein and transports proteins in the blood stream but is also highly expressed in human hepatocytes and cholangiocytes 38,39 . Its isoform ORM2 regulates de novo lipogenesis, one of the most important mechanisms of MASLD, in the mouse liver, which may indicate the potential causal association of ORM1 and MASLD 58,59 . A few studies have reported the potential association of Adenosylhomocysteinase (AHCY) 60 and Fc gamma receptor IIb (FCGR2B) with MASLD 61,62 .…”

Section: Discussionmentioning

confidence: 99%

Profiling the genome and proteome of metabolic dysfunction-associated steatotic liver disease identifies potential therapeutic targets

Liu,

Hu,

Chen

et al. 2023

Preprint

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BACKGROUND & AIMSMetabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the population and currently has no effective treatments. Plasma proteins with causal evidence may represent promising drug targets. We aimed to identify plasma proteins in the causal pathway of MASLD and explore their interaction with obesity.METHODSWe analysed 2,941 plasma proteins in 43,978 European participants from UK Biobank. We performed genome-wide association study (GWAS) for all MASLD-associated proteins and created the largest MASLD GWAS (109,885 cases/1,014,923 controls). We performed Mendelian Randomization (MR) and integrated proteins and their encoding genes in MASLD ranges to identify candidate causal proteins. We then validated them through independent replication, exome sequencing, liver imaging, bulk and single-cell gene expression, liver biopsies, pathway, and phenome-wide data. We explored the role of obesity by MR and multivariable MR across proteins, body mass index, and MASLD.RESULTSWe found 929 proteins associated with MASLD, reported five novel genetic loci associated with MASLD, and identified 17 candidate MASLD protein targets. We identified four novel targets for MASLD (CD33, GRHPR, HMOX2, and SCG3), provided protein evidence supporting roles of AHCY, FCGR2B, ORM1, and RBKS in MASLD, and validated nine previously known targets. We found that CD33, FCGR2B, ORM1, RBKS, and SCG3 mediated the association of obesity and MASLD, and HMOX2, ORM1, and RBKS had effect on MASLD independent of obesity.CONCLUSIONSThis study identified new protein targets in the causal pathway of MASLD, providing new insights into the multi-omics architecture and pathophysiology of MASLD. These findings advise further therapeutic interventions for MASLD.

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Orm2 Deficiency Aggravates High‐Fat Diet‐Induced Obesity through Gut Microbial Dysbiosis and Intestinal Inflammation

Li,

Chen,

Sun

et al. 2023

Molecular Nutrition Food Res

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ScopeOrosomucoid 2 (Orm2) is a hepatocyte‐secreted protein that plays a crucial role in regulating obesity‐type metabolic disease and immunity. The imbalance of gut microbiota is one of the causes of obesity, but the mechanism of the relationship between Orm2 and gut microbiota in obesity remains unclear.Methods and resultsOrm2‐/‐ (Orm2 knockout) mice on a normal diet developed spontaneous obesity and metabolic disturbances at the 20th week. Through 16S rRNA gene sequencing, the study finds that the gut microbiota of Orm2‐/‐ mice has a different microbial composition compared to wild type (WT) mice. Furthermore, a high‐fat diet (HFD) for 16 weeks exacerbates obesity in Orm2‐/‐ mice. Lack of Orm2 promotes dysregulation of gut microbiota under the HFD, especially a reduction of Clostridium spp. Supplementation with Clostridium butyricum alleviates obesity and alters the gut microbial composition in WT mice, but has minimal effects on Orm2‐/‐ mice. In contrast, co‐housing of Orm2‐/‐ mice with WT mice rescues Orm2‐/‐ obesity by reducing pathogenic bacteria and mitigating intestinal inflammation.ConclusionThese findings suggest Orm2 deficiency exacerbates HFD‐induced gut microbiota disturbance and intestinal inflammation, providing a novel insight into the complex bacterial flora but not a single probiotic administration in the therapeutic strategy of obesity.

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Mitigation of non-alcoholic steatohepatitis via recombinant Orosomucoid 2, an acute phase protein modulating the Erk1/2-PPARγ-Cd36 pathway

Cited by 6 publications

References 43 publications

Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach

Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach

Profiling the genome and proteome of metabolic dysfunction-associated steatotic liver disease identifies potential therapeutic targets

Orm2 Deficiency Aggravates High‐Fat Diet‐Induced Obesity through Gut Microbial Dysbiosis and Intestinal Inflammation

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