Prevention of cardiovascular disease (CVD) is one of the main objectives in the management of people with type 2 diabetes (T2DM). New glucose-lowering therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated not only cardiovascular safety but also cardiovascular benefits. In line with emerging evidence from the cardiovascular outcome trials (CVOTs), major international guidelines advocate GLP-1RAs and SGLT-2 inhibitors with proven cardiovascular benefits as a first add-on or monotherapy in individuals with T2DM and established CVD or CVD risk factors. Based on subsequent cardiorenal outcomes and heart failure trials, the licensed indications of some SGLT-2 inhibitors have been extended beyond glycaemic management. SGLT-2 inhibitors have now been approved for the management of chronic heart failure and chronic kidney disease, both irrespective of diabetes status. This review aims to summarise the CVOTs of GLP-1RAs and SGLT-2 inhibitors from the clinician’s perspective.
{"title":"Cardiovascular outcome trials of GLP-1RAs and SGLT-2 inhibitors: a concise review from the clinicians’ perspective","authors":"T. Min, E. Crockett, A. Pavlou, Stephen C. Bain","doi":"10.20517/mtod.2023.09","DOIUrl":"https://doi.org/10.20517/mtod.2023.09","url":null,"abstract":"Prevention of cardiovascular disease (CVD) is one of the main objectives in the management of people with type 2 diabetes (T2DM). New glucose-lowering therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated not only cardiovascular safety but also cardiovascular benefits. In line with emerging evidence from the cardiovascular outcome trials (CVOTs), major international guidelines advocate GLP-1RAs and SGLT-2 inhibitors with proven cardiovascular benefits as a first add-on or monotherapy in individuals with T2DM and established CVD or CVD risk factors. Based on subsequent cardiorenal outcomes and heart failure trials, the licensed indications of some SGLT-2 inhibitors have been extended beyond glycaemic management. SGLT-2 inhibitors have now been approved for the management of chronic heart failure and chronic kidney disease, both irrespective of diabetes status. This review aims to summarise the CVOTs of GLP-1RAs and SGLT-2 inhibitors from the clinician’s perspective.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67659217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Obesity-related gonadal dysfunction in males has been defined recently as male obesity secondary hypogonadism (MOSH). Affected individuals present with signs and symptoms related to the sex hormone imbalance but also with a burden of metabolic risk factors and occasionally compromised fertility. In pathophysiological terms, excess body fat is associated with leptin and insulin resistance. Accelerated synthesis of leptin and hyperinsulinemia downregulate the expression of kisspeptin receptors and, consequently, the action of kisspeptin. This critical neuropeptide is known to control gonadotropin secretion. In obese males, enhanced activity of the aromatase enzyme is associated with an increase in the conversion of circulating testosterone to estrogen, further promoting a state of hypogonadism. In addition, high fat and low fiber intake alter the intestinal microbiome and the dysfunction of the gut-brain axis. Weight loss appears to be the key to readjusting the function of the hypothalamus-pituitary-gonadal axis. It can be achieved with lifestyle measures in combination with weight loss medications or bariatric surgery. The degree of weight loss appears to resolve the symptoms related to hypogonadism and improve fertility chances. However, the role of hormone replacement is also important, as testosterone replacement has been shown to reduce fat mass and increase the amount of lean body mass while also contributing to weight loss and the regulation of body mass index and waist circumference. This narrative review analyzes the evidence on developing obesity-related endocrinopathies and the available management options. Further research is required to estimate the cut-off of body mass index associated with a higher risk for hypogonadism.
{"title":"Male hypogonadism in overweight and obesity","authors":"E. Armeni","doi":"10.20517/mtod.2023.05","DOIUrl":"https://doi.org/10.20517/mtod.2023.05","url":null,"abstract":"Obesity-related gonadal dysfunction in males has been defined recently as male obesity secondary hypogonadism (MOSH). Affected individuals present with signs and symptoms related to the sex hormone imbalance but also with a burden of metabolic risk factors and occasionally compromised fertility. In pathophysiological terms, excess body fat is associated with leptin and insulin resistance. Accelerated synthesis of leptin and hyperinsulinemia downregulate the expression of kisspeptin receptors and, consequently, the action of kisspeptin. This critical neuropeptide is known to control gonadotropin secretion. In obese males, enhanced activity of the aromatase enzyme is associated with an increase in the conversion of circulating testosterone to estrogen, further promoting a state of hypogonadism. In addition, high fat and low fiber intake alter the intestinal microbiome and the dysfunction of the gut-brain axis. Weight loss appears to be the key to readjusting the function of the hypothalamus-pituitary-gonadal axis. It can be achieved with lifestyle measures in combination with weight loss medications or bariatric surgery. The degree of weight loss appears to resolve the symptoms related to hypogonadism and improve fertility chances. However, the role of hormone replacement is also important, as testosterone replacement has been shown to reduce fat mass and increase the amount of lean body mass while also contributing to weight loss and the regulation of body mass index and waist circumference. This narrative review analyzes the evidence on developing obesity-related endocrinopathies and the available management options. Further research is required to estimate the cut-off of body mass index associated with a higher risk for hypogonadism.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67659207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Ballestri, A. Mantovani, M. Girolamo, E. Baldelli, M. Capitelli, A. Lonardo
Liver fibrosis is critical for liver-related outcomes and mortality in chronic liver disease, irrespective of etiology, including nonalcoholic fatty liver disease (NAFLD). NAFLD has been viewed as an independent correlate of cardiovascular risk. This review article briefly describes the cellular and molecular pathomechanisms underlying hepatic fibrosis. We then address noninvasive assessment of liver fibrosis. Finally, we discuss published evidence supporting fibrosis biomarkers’ role in assessing cardiovascular risk among patients with NAFLD. While histological assessment is the diagnostic standard of hepatic fibrosis, we specifically address noninvasive techniques, including equations based on anthropometric parameters, laboratory indices, and elastometry obtained with imaging techniques. The former group includes AST: ALT ratio, the Forns Index, the AST-to-platelet ratio index score, BARD (BMI, AAR, Diabetes) score, the fibrosis-4 index (FIB-4), the NAFLD fibrosis score, the gamma-glutamyl transferase-to-platelet ratio, and the Hepamet fibrosis score. The latter comprises elastographic techniques associated with ultrasonography or magnetic resonance. Our literature review identified numerous studies demonstrating that biomarkers of fibrosis (the most common being FIB-4) and elastographic techniques predict overall mortality and major cardiovascular events among NAFLD patients. The mechanisms accounting for this association are briefly reviewed. In addition to assessing hepatic fibrosis at baseline, during follow-up, and after therapeutic interventions in NAFLD patients, noninvasive assessment of hepatic fibrosis may predict cardiovascular events and overall mortality in these patients.
{"title":"Liver fibrosis in nonalcoholic fatty liver disease patients: noninvasive evaluation and correlation with cardiovascular disease and mortality","authors":"S. Ballestri, A. Mantovani, M. Girolamo, E. Baldelli, M. Capitelli, A. Lonardo","doi":"10.20517/mtod.2022.23","DOIUrl":"https://doi.org/10.20517/mtod.2022.23","url":null,"abstract":"Liver fibrosis is critical for liver-related outcomes and mortality in chronic liver disease, irrespective of etiology, including nonalcoholic fatty liver disease (NAFLD). NAFLD has been viewed as an independent correlate of cardiovascular risk. This review article briefly describes the cellular and molecular pathomechanisms underlying hepatic fibrosis. We then address noninvasive assessment of liver fibrosis. Finally, we discuss published evidence supporting fibrosis biomarkers’ role in assessing cardiovascular risk among patients with NAFLD. While histological assessment is the diagnostic standard of hepatic fibrosis, we specifically address noninvasive techniques, including equations based on anthropometric parameters, laboratory indices, and elastometry obtained with imaging techniques. The former group includes AST: ALT ratio, the Forns Index, the AST-to-platelet ratio index score, BARD (BMI, AAR, Diabetes) score, the fibrosis-4 index (FIB-4), the NAFLD fibrosis score, the gamma-glutamyl transferase-to-platelet ratio, and the Hepamet fibrosis score. The latter comprises elastographic techniques associated with ultrasonography or magnetic resonance. Our literature review identified numerous studies demonstrating that biomarkers of fibrosis (the most common being FIB-4) and elastographic techniques predict overall mortality and major cardiovascular events among NAFLD patients. The mechanisms accounting for this association are briefly reviewed. In addition to assessing hepatic fibrosis at baseline, during follow-up, and after therapeutic interventions in NAFLD patients, noninvasive assessment of hepatic fibrosis may predict cardiovascular events and overall mortality in these patients.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67659411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Association between type 2 diabetes mellitus and prostate cancer","authors":"Zhiwei Wang, Guiping Yao, Bing Yan, Chenghao Zhanghuang","doi":"10.20517/mtod.2023.34","DOIUrl":"https://doi.org/10.20517/mtod.2023.34","url":null,"abstract":"","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135551215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Are hepatocytes endocrine cells?","authors":"Yan Lu, M. Zheng, Hua Wang","doi":"10.20517/mtod.2023.11","DOIUrl":"https://doi.org/10.20517/mtod.2023.11","url":null,"abstract":"","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67659226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Metabolic bariatric surgery in face of new anti-obesity medications-10 + 1 challenges","authors":"Athanasios G. Pantelis, Dimitris P. Lapatsanis","doi":"10.20517/mtod.2023.27","DOIUrl":"https://doi.org/10.20517/mtod.2023.27","url":null,"abstract":"","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"165 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136367324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This commentary is devoted to a recent study by Ren and Zheng (Nutr Metab Cardiovasc Dis. 2023;33:1349-1357). These authors analyzed sex-stratified long-term outcomes relevant to all-cause and cardiovascular field outcomes among 2,627 nonalcoholic fatty liver disease (NAFLD) adults enrolled in the 2000-2014 National Health and Nutrition Examination Surveys and identified with United States Fatty Liver Index (US FLI) score. Data have shown that, compared to women, men were exposed to a significantly higher all-cause mortality and the maximal risk was seen among those who had obesity and type 2 diabetes. However, women aged ≤ 60 years had a higher risk of death owing to cardiovascular disease (CVD). Conversely, no significantly increased risk of death from CVD was observed among women over 60 years compared to men of the same age group. The study by Ren and Zheng further fosters our understanding of cardiometabolic risk factors, illustrating sex differences present in NAFLD. The distinct impact of NAFLD on CVD by sex and age suggests that cardiometabolic comorbidities may be particularly underestimated among young and middle-aged women with NAFLD. The research by Ren and Zhang may stimulate future investigations exploring the molecular and cellular grounds underlying these findings, notably including the role of fibrosing NAFLD as a strong risk modifier of CVD. In conclusion, an improved understanding of sex-specific regulation of human metabolism in the liver and other key metabolic organs is a research priority finalized for implementing precision medicine approaches in NAFLD arena.
{"title":"Commentary: Of women, liver, and heart","authors":"Jun Wang, Amedeo Lonardo","doi":"10.20517/mtod.2023.23","DOIUrl":"https://doi.org/10.20517/mtod.2023.23","url":null,"abstract":"This commentary is devoted to a recent study by Ren and Zheng (Nutr Metab Cardiovasc Dis. 2023;33:1349-1357). These authors analyzed sex-stratified long-term outcomes relevant to all-cause and cardiovascular field outcomes among 2,627 nonalcoholic fatty liver disease (NAFLD) adults enrolled in the 2000-2014 National Health and Nutrition Examination Surveys and identified with United States Fatty Liver Index (US FLI) score. Data have shown that, compared to women, men were exposed to a significantly higher all-cause mortality and the maximal risk was seen among those who had obesity and type 2 diabetes. However, women aged ≤ 60 years had a higher risk of death owing to cardiovascular disease (CVD). Conversely, no significantly increased risk of death from CVD was observed among women over 60 years compared to men of the same age group. The study by Ren and Zheng further fosters our understanding of cardiometabolic risk factors, illustrating sex differences present in NAFLD. The distinct impact of NAFLD on CVD by sex and age suggests that cardiometabolic comorbidities may be particularly underestimated among young and middle-aged women with NAFLD. The research by Ren and Zhang may stimulate future investigations exploring the molecular and cellular grounds underlying these findings, notably including the role of fibrosing NAFLD as a strong risk modifier of CVD. In conclusion, an improved understanding of sex-specific regulation of human metabolism in the liver and other key metabolic organs is a research priority finalized for implementing precision medicine approaches in NAFLD arena.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135551087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mechanobiology is a rapidly emerging field focused on the biological impact of physical forces at the molecular, cellular, and tissue level. Living cells perceive mechanical cues and transform them into biochemical signals through mechanotransduction. Mechanotransduction is a complex process that involves mechanosensors (which are located in the plasma membrane or within the cell) and mechanotransmission to the nucleus (which occurs either by physical connection between the mechanosensor and the nucleus or by mechanosignaling through biochemical pathways). Essential biological functions, including development, growth, motility, and metabolism, depend on the mechanoresponses generated by these events. Multiple lines of evidence indicate that disruption of mechanical homeostasis may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a highly prevalent metabolic disorder characterized by abnormal accumulation of lipid droplets in hepatocytes (steatosis) and often associated with inflammation and liver cell injury (steatohepatitis). While predicting individual predisposition to adverse outcomes in NAFLD remains a challenge, there is increasing evidence that steatosis and steatohepatitis trigger mechanoresponses that contribute to the early stages of pathogenesis in NAFLD and critically impact disease progression. Lipid accumulation and lipotoxicity modify liver viscoelasticity, alter the biomechanics of liver sinusoids, and initiate aberrant pathways of mechanotransduction in hepatocytes and non-parenchymal liver cells, such as sinusoidal endothelial cells and hepatic stellate cells. Interactions of these cells at mechanical interfaces with each other, with extracellular matrix, and with sinusoidal blood flow are profoundly altered by steatosis and steatohepatitis; such changes may promote a pro-angiogenic and pro-fibrotic milieu. A better understanding of liver mechanobiology may facilitate the identification of novel molecular and cellular targets in the management of NAFLD.
{"title":"Mechanobiology in the development and progression of non-alcoholic fatty liver disease: an updated review","authors":"Emilie K. Mitten, G. Baffy","doi":"10.20517/mtod.2022.37","DOIUrl":"https://doi.org/10.20517/mtod.2022.37","url":null,"abstract":"Mechanobiology is a rapidly emerging field focused on the biological impact of physical forces at the molecular, cellular, and tissue level. Living cells perceive mechanical cues and transform them into biochemical signals through mechanotransduction. Mechanotransduction is a complex process that involves mechanosensors (which are located in the plasma membrane or within the cell) and mechanotransmission to the nucleus (which occurs either by physical connection between the mechanosensor and the nucleus or by mechanosignaling through biochemical pathways). Essential biological functions, including development, growth, motility, and metabolism, depend on the mechanoresponses generated by these events. Multiple lines of evidence indicate that disruption of mechanical homeostasis may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a highly prevalent metabolic disorder characterized by abnormal accumulation of lipid droplets in hepatocytes (steatosis) and often associated with inflammation and liver cell injury (steatohepatitis). While predicting individual predisposition to adverse outcomes in NAFLD remains a challenge, there is increasing evidence that steatosis and steatohepatitis trigger mechanoresponses that contribute to the early stages of pathogenesis in NAFLD and critically impact disease progression. Lipid accumulation and lipotoxicity modify liver viscoelasticity, alter the biomechanics of liver sinusoids, and initiate aberrant pathways of mechanotransduction in hepatocytes and non-parenchymal liver cells, such as sinusoidal endothelial cells and hepatic stellate cells. Interactions of these cells at mechanical interfaces with each other, with extracellular matrix, and with sinusoidal blood flow are profoundly altered by steatosis and steatohepatitis; such changes may promote a pro-angiogenic and pro-fibrotic milieu. A better understanding of liver mechanobiology may facilitate the identification of novel molecular and cellular targets in the management of NAFLD.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67659083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Primary liver cancer (PLC) is a heterogeneous group of disorders arising with the background of chronic liver disease (CLD) owing to varying etiologies. PLC carries a high lethality rate and a substantial epidemiological, clinical, and financial burden, which is projected to escalate. The two most common PLC histotypes in adults are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC); the latter is sub-classified as either intrahepatic CC or extrahepatic CC. Over recent decades, there has been a decline of viral CLD accompanied by an increase in dysmetabolic CLD, resulting in PLC becoming relatively more common in Western countries. Metabolic co-morbidities are risk factors and co-factors for HCC and (increasingly) CC. Complex immunological, cellular, pro-inflammatory, molecular, and genetic processes in the systemic dysmetabolic milieu increase PLC risk. Improved understanding of these mechanisms requires close surveillance and early diagnosis of at-risk patients while paving the way for personalized medicine, chemoprevention, and innovative management of metabolic PLC.
{"title":"Metabolic primary liver cancer in adults: risk factors and pathogenic mechanisms","authors":"S. Lugari, E. Baldelli, A. Lonardo","doi":"10.20517/mtod.2022.38","DOIUrl":"https://doi.org/10.20517/mtod.2022.38","url":null,"abstract":"Primary liver cancer (PLC) is a heterogeneous group of disorders arising with the background of chronic liver disease (CLD) owing to varying etiologies. PLC carries a high lethality rate and a substantial epidemiological, clinical, and financial burden, which is projected to escalate. The two most common PLC histotypes in adults are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC); the latter is sub-classified as either intrahepatic CC or extrahepatic CC. Over recent decades, there has been a decline of viral CLD accompanied by an increase in dysmetabolic CLD, resulting in PLC becoming relatively more common in Western countries. Metabolic co-morbidities are risk factors and co-factors for HCC and (increasingly) CC. Complex immunological, cellular, pro-inflammatory, molecular, and genetic processes in the systemic dysmetabolic milieu increase PLC risk. Improved understanding of these mechanisms requires close surveillance and early diagnosis of at-risk patients while paving the way for personalized medicine, chemoprevention, and innovative management of metabolic PLC.","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67659093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01Epub Date: 2022-10-25DOI: 10.20517/mtod.2022.13
Adam Kim, Christina K Cajigas-Du Ross, Jaividhya Dasarathy, Annette Bellar, David Streem, Nicole Welch, Srinivasan Dasarathy, Laura E Nagy
Aim: Metabolic liver diseases, including alcohol- and non-alcoholic fatty liver diseases (ALD/NAFLD), are characterized by inflammation and decreased ability to prevent infections. Patients with severe alcohol-associated hepatitis (sAH) are particularly susceptible to infections while undergoing treatment with steroids. Understanding the immunological mechanisms for these responses is critical to managing the treatment of patients with metabolic liver diseases. Cytotoxic NK cells and CD8 T cells, using cytolytic granules, serve an important immunological role by killing infected cells, including monocytes. However, patients with sAH have dysfunctional NK cells, which cannot kill target cells, though the mechanism is unknown.
Method: We performed an exploratory study using single-cell RNA-seq (scRNA-seq) (n = 4) and multi-panel intracellular flow cytometry (n = 7-8 for all patient groups) on PBMCs isolated from patients with sAH and healthy controls (HC).
Results: ScRNA-seq revealed receptors in NK cells and CD8 T cells required for cytotoxic cell recognition of activated monocytes were downregulated in patients with sAH compared to healthy controls. Granulysin was the most downregulated gene in both NK cells and effector CD8 T cells. In NK cells from HC, expression of granulysin, perforin, and granzymes A and B was highly correlated; however, in sAH, these genes lost coordinate expression, indicative of dysfunctional cytolytic granule formation. Finally, the expression of cytolytic granule proteins in NK cells was decreased from sAH, indicating reduced cytolytic granules.
Conclusion: Together, these results suggest a loss of cytotoxic cell function in PBMCs from sAH that may contribute to a decreased ability to communicate with other immune cells, such as monocytes, and prevent the killing of infected cells, thus increasing the risk of infection.
目的：代谢性肝病，包括酒精肝和非酒精性脂肪肝（ALD/NAFLD），以炎症和预防感染能力下降为特征。严重酒精相关性肝炎（sAH）患者在接受类固醇治疗期间尤其容易受到感染。了解这些反应的免疫机制对于代谢性肝病患者的治疗至关重要。细胞毒性 NK 细胞和 CD8 T 细胞利用细胞溶解颗粒杀死受感染的细胞（包括单核细胞），从而发挥重要的免疫作用。然而，sAH 患者的 NK 细胞功能失调，无法杀死靶细胞，但其机制尚不清楚：我们使用单细胞 RNA-seq（scRNA-seq）（n = 4）和多面板细胞内流式细胞仪（n = 7-8，适用于所有患者组）对分离自 sAH 患者和健康对照组（HC）的 PBMCs 进行了一项探索性研究：ScRNA-seq显示，与健康对照组相比，sAH患者NK细胞和CD8 T细胞中细胞毒性细胞识别活化单核细胞所需的受体被下调。在NK细胞和效应CD8 T细胞中，Granulysin是下调幅度最大的基因。在 HC 的 NK 细胞中，粒细胞溶素、穿孔素以及粒酶 A 和 B 的表达高度相关；但在 sAH 中，这些基因失去了协调表达，表明细胞溶解颗粒的形成功能失调。最后，NK 细胞中细胞溶解颗粒蛋白的表达比 sAH 减少，表明细胞溶解颗粒减少：总之，这些结果表明，sAH 患者的 PBMC 细胞毒性细胞功能丧失，可能会导致与其他免疫细胞（如单核细胞）交流的能力下降，并阻止杀死感染细胞，从而增加感染风险。
{"title":"Diminished function of cytotoxic T- and NK- cells in severe alcohol-associated hepatitis.","authors":"Adam Kim, Christina K Cajigas-Du Ross, Jaividhya Dasarathy, Annette Bellar, David Streem, Nicole Welch, Srinivasan Dasarathy, Laura E Nagy","doi":"10.20517/mtod.2022.13","DOIUrl":"10.20517/mtod.2022.13","url":null,"abstract":"<p><strong>Aim: </strong>Metabolic liver diseases, including alcohol- and non-alcoholic fatty liver diseases (ALD/NAFLD), are characterized by inflammation and decreased ability to prevent infections. Patients with severe alcohol-associated hepatitis (sAH) are particularly susceptible to infections while undergoing treatment with steroids. Understanding the immunological mechanisms for these responses is critical to managing the treatment of patients with metabolic liver diseases. Cytotoxic NK cells and CD8 T cells, using cytolytic granules, serve an important immunological role by killing infected cells, including monocytes. However, patients with sAH have dysfunctional NK cells, which cannot kill target cells, though the mechanism is unknown.</p><p><strong>Method: </strong>We performed an exploratory study using single-cell RNA-seq (scRNA-seq) (<i>n</i> = 4) and multi-panel intracellular flow cytometry (<i>n</i> = 7-8 for all patient groups) on PBMCs isolated from patients with sAH and healthy controls (HC).</p><p><strong>Results: </strong>ScRNA-seq revealed receptors in NK cells and CD8 T cells required for cytotoxic cell recognition of activated monocytes were downregulated in patients with sAH compared to healthy controls. Granulysin was the most downregulated gene in both NK cells and effector CD8 T cells. In NK cells from HC, expression of granulysin, perforin, and granzymes A and B was highly correlated; however, in sAH, these genes lost coordinate expression, indicative of dysfunctional cytolytic granule formation. Finally, the expression of cytolytic granule proteins in NK cells was decreased from sAH, indicating reduced cytolytic granules.</p><p><strong>Conclusion: </strong>Together, these results suggest a loss of cytotoxic cell function in PBMCs from sAH that may contribute to a decreased ability to communicate with other immune cells, such as monocytes, and prevent the killing of infected cells, thus increasing the risk of infection.</p>","PeriodicalId":91001,"journal":{"name":"Metabolism and target organ damage","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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