1.Korean Society of Nephrology 2022 Recommendations on controversial issues in diagnosis and management ofhyponatremia
Yeonhee LEE ; Kyung Don YOO ; Seon Ha BAEK ; Yang Gyun KIM ; Hyo Jin KIM ; Ji Young RYU ; Jin Hyuk PAEK ; Sang Heon SUH ; Se Won OH ; Jeonghwan LEE ; Jong Hyun JHEE ; Jin-Soon SUH ; Eun Mi YANG ; Young Ho PARK ; Yae Lim KIM ; Miyoung CHOI ; Kook-Hwan OH ; Sejoong KIM ;
Kidney Research and Clinical Practice 2022;41(4):393-411
The Korean Society for Electrolyte and Blood Pressure Research, in collaboration with the Korean Society of Nephrology, has published a clinical practice guideline (CPG) document for hyponatremia treatment. The document is based on an extensive evidence-based review of the diagnosis, evaluation, and treatment of hyponatremia with the multidisciplinary participation of representative experts in hyponatremia with methodologist support for guideline development. This CPG consists of 12 recommendations (two for diagnosis, eight for treatment, and two for special situations) based on eight detailed topics and nine key questions. Each recommendation begins with statements graded by the strength of the recommendations and the quality of the evidence. Each statement is followed by rationale supporting the recommendations. The committee issued conditional recommendations in favor of rapid intermittent bolus administration of hypertonic saline in severe hyponatremia, the use of vasopressin receptor antagonists in heart failure with hypervolemic hyponatremia, and syndrome of inappropriate antidiuresis with moderate to severe hyponatremia, the individualization of desmopressin use, and strong recommendation on the administration of isotonic fluids as maintenance fluid therapy in hospitalized pediatric patients. We hope that this CPG will provide useful recommendations in practice, with the aim of providing clinical support for shared decision-making to improve patient outcomes.
2.Korean Society of Nephrology 2022 recommendations on controversial issues in diagnosis and management of hyponatremia
Yeonhee LEE ; Kyung Don YOO ; Seon Ha BAEK ; Yang Gyun KIM ; Hyo Jin KIM ; Ji Young RYU ; Jin Hyuk PAEK ; Sang Heon SUH ; Se Won OH ; Jeonghwan LEE ; Jong Hyun JHEE ; Jin-Soon SUH ; Eun Mi YANG ; Young Ho PARK ; Yae Lim KIM ; Miyoung CHOI ; Kook-Hwan OH ; Sejoong KIM ;
The Korean Journal of Internal Medicine 2022;37(6):1120-1137
The Korean Society for Electrolyte and Blood Pressure Research, in collaboration with the Korean Society of Nephrology, has published a clinical practice guideline (CPG) document for hyponatremia treatment. The document is based on an extensive evidence-based review of the diagnosis, evaluation, and treatment of hyponatremia with the multidisciplinary participation of representative experts in hyponatremia with methodologist support for guideline development. This CPG consists of 12 recommendations (two for diagnosis, eight for treatment, and two for special situations) based on eight detailed topics and nine key questions. Each recommendation begins with statements graded by the strength of the recommendations and the quality of the evidence. Each statement is followed by rationale supporting the recommendations. The committee issued conditional recommendations in favor of rapid intermittent bolus administration of hypertonic saline in severe hyponatremia, the use of vasopressin receptor antagonists in heart failure with hypervolemic hyponatremia, and syndrome of inappropriate antidiuresis with moderate to severe hyponatremia, the individualization of desmopressin use, and strong recommendation on the administration of isotonic fluids as maintenance fluid therapy in hospitalized pediatric patients. We hope that this CPG will provide useful recommendations in practice, with the aim of providing clinical support for shared decision-making to improve patient outcomes.
3.Reappraisal of sepsis-3 and CLIF-SOFA as predictors of mortality in patients with cirrhosis and infection presenting to the emergency department: A multicenter study
Ji Hyun KIM ; Baek Gyu JUN ; Minjong LEE ; Hye Ah LEE ; Tae Suk KIM ; Jeong Won HEO ; Da Hye MOON ; Seong Hee KANG ; Ki Tae SUK ; Moon Young KIM ; Young Don KIM ; Gab Jin CHEON ; Soon Koo BAIK ; Dong Joon KIM ; Dae Hee CHOI
Clinical and Molecular Hepatology 2022;28(3):540-552
Background/Aims:
Sepsis-3 criteria and quick Sequential Organ Failure Assessment (qSOFA) have been advocated to be used in defining sepsis in the general population. We aimed to compare the Sepsis-3 criteria and Chronic Liver Failure-SOFA (CLIF-SOFA) scores as predictors of in-hospital mortality in cirrhotic patients admitted to the emergency department (ED) for infections.
Methods:
A total of 1,622 cirrhosis patients admitted at the ED for infections were assessed retrospectively. We analyzed their demographic, laboratory, and microbiological data upon diagnosis of the infection. The primary endpoint was inhospital mortality rate. The predictive performances of baseline CLIF-SOFA, Sepsis-3, and qSOFA scores for in-hospital mortality were evaluated.
Results:
The CLIF-SOFA score proved to be significantly better in predicting in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.80; 95% confidence interval [CI], 0.78–0.82) than the Sepsis-3 (AUROC, 0.75; 95% CI, 0.72–0.77, P<0.001) and qSOFA (AUROC, 0.67; 95% CI, 0.64–0.70; P<0.001) score. The CLIF-SOFA, CLIF-C-AD scores, Sepsis-3 criteria, septic shock, and qSOFA positivity were significantly associated with in-hospital mortality (adjusted hazard ratio [aHR], 1.24; 95% CI, 1.19–1.28; aHR, 1.13; 95% CI, 1.09–1.17; aHR, 1.19; 95% CI, 1.15–1.24; aHR, 1.88; 95% CI, 1.42–2.48; aHR, 2.06; 95% CI, 1.55–2.72; respectively; all P<0.001). For CLIF-SOFA scores ≥6, in-hospital mortality was >10%; this is the cutoff point for the definition of sepsis.
Conclusions
Among cirrhosis patients presenting with infections at the ED, CLIF-SOFA scores showed a better predictive performance for mortality than both Sepsis-3 criteria and qSOFA scores, and can be a useful tool of risk stratification in cirrhotic patients requiring timely intervention for infection.
4.Clinical Practice Guideline for Cardiac Rehabilitation in Korea: Recommendations for Cardiac Rehabilitation and Secondary Prevention after Acute Coronary Syndrome
Chul KIM ; Jidong SUNG ; Jong Hwa LEE ; Won Seok KIM ; Goo Joo LEE ; Sungju JEE ; Il Young JUNG ; Ueon Woo RAH ; Byung Ok KIM ; Kyoung Hyo CHOI ; Bum Sun KWON ; Seung Don YOO ; Heui Je BANG ; Hyung Ik SHIN ; Yong Wook KIM ; Heeyoune JUNG ; Eung Ju KIM ; Jung Hwan LEE ; In Hyun JUNG ; Jae Seung JUNG ; Jong Young LEE ; Jae Young HAN ; Eun Young HAN ; Yu Hui WON ; Woosik HAN ; Sora BAEK ; Kyung Lim JOA ; Sook Joung LEE ; Ae Ryoung KIM ; So Young LEE ; Jihee KIM ; Hee Eun CHOI ; Byeong Ju LEE ; Soon KIM
Korean Circulation Journal 2019;49(11):1066-1111
Though clinical practice guidelines (CPGs) for cardiac rehabilitation (CR) are an effective and widely used treatment method worldwide, they are as yet not widely accepted in Korea. Given that cardiovascular (CV) disease is the second leading cause of death in Korea, it is urgent that CR programs be developed. In 2008, the Government of Korea implemented CR programs at 11 university hospitals as part of its Regional Cardio-Cerebrovascular Center Project, and 3 additional medical facilities will be added in 2019. In addition, owing to the promotion of CR nationwide and the introduction of CR insurance benefits, 40 medical institutions nationwide have begun CR programs even as a growing number of medical institutions are preparing to offer CR. The purpose of this research was to develop evidence-based CPGs to support CR implementation in Korea. This study is based on an analysis of CPGs elsewhere in the world, an extensive literature search, a systematic analysis of multiple randomized control trials, and a CPG management, development, and assessment committee comprised of thirty-three authors—primarily rehabilitation specialists, cardiologists, and thoracic surgeons in 21 university hospitals and 2 general hospitals. Twelve consultants, primarily rehabilitation, sports medicine, and preventive medicine specialists, CPG experts, nurses, physical therapists, clinical nutritionists, and library and information experts participated in the research and development of these CPGs. After the draft guidelines were developed, 3 rounds of public hearings were held with staff members from relevant academic societies and stakeholders, after which the guidelines were further reviewed and modified. CR involves a more cost-effective use of healthcare resources relative to that of general treatments, and the exercise component of CR lowers CV mortality and readmission rates, regardless of the type of coronary heart disease and type and setting of CR. Individualized CR programs should be considered together with various factors, including differences in heart function and lifestyle, and doing so will boost participation and adherence with the CR program, ultimately meeting the final goals of the program, namely reducing the recurrence of myocardial infarction and mortality rates.
Acute Coronary Syndrome
;
Cause of Death
;
Consultants
;
Coronary Disease
;
Delivery of Health Care
;
Heart
;
Hospitals, General
;
Hospitals, University
;
Humans
;
Insurance Benefits
;
Korea
;
Life Style
;
Methods
;
Mortality
;
Myocardial Infarction
;
Nutritionists
;
Physical Therapists
;
Preventive Medicine
;
Recurrence
;
Rehabilitation
;
Secondary Prevention
;
Specialization
;
Sports Medicine
;
Surgeons
5.Clinical Practice Guideline for Cardiac Rehabilitation in Korea
Chul KIM ; Jidong SUNG ; Jong Hwa LEE ; Won Seok KIM ; Goo Joo LEE ; Sungju JEE ; Il Young JUNG ; Ueon Woo RAH ; Byung Ok KIM ; Kyoung Hyo CHOI ; Bum Sun KWON ; Seung Don YOO ; Heui Je BANG ; Hyung Ik SHIN ; Yong Wook KIM ; Heeyoune JUNG ; Eung Ju KIM ; Jung Hwan LEE ; In Hyun JUNG ; Jae Seung JUNG ; Jong Young LEE ; Jae Young HAN ; Eun Young HAN ; Yu Hui WON ; Woosik HAN ; Sora BAEK ; Kyung Lim JOA ; Sook Joung LEE ; Ae Ryoung KIM ; So Young LEE ; Jihee KIM ; Hee Eun CHOI ; Byeong Ju LEE ; Soon KIM
The Korean Journal of Thoracic and Cardiovascular Surgery 2019;52(4):248-285
BACKGROUND: Though clinical practice guidelines (CPGs) for cardiac rehabilitation (CR) are an effective and widely used treatment method worldwide, they are as yet not widely accepted in Korea. Given that cardiovascular disease is the second leading cause of death in Korea, it is urgent that CR programs be developed. In 2008, the Government of Korea implemented CR programs at 11 university hospitals as part of its Regional Cardio-Cerebrovascular Center Project, and 3 additional medical facilities will be added in 2019. In addition, owing to the promotion of CR nationwide and the introduction of CR insurance benefits, 40 medical institutions nationwide have begun CR programs even as a growing number of medical institutions are preparing to offer CR. The purpose of this research was to develop evidence-based CPGs to support CR implementation in Korea. METHODS: This study is based on an analysis of CPGs elsewhere in the world, an extensive literature search, a systematic analysis of multiple randomized control trials, and a CPG management, development, and assessment committee comprised of 33 authors—primarily rehabilitation specialists, cardiologists, and thoracic surgeons in 21 university hospitals and 2 general hospitals. Twelve consultants, primarily rehabilitation, sports medicine, and preventive medicine specialists, CPG experts, nurses, physical therapists, clinical nutritionists, and library and information experts participated in the research and development of these CPGs. After the draft guidelines were developed, 3 rounds of public hearings were held with staff members from relevant academic societies and stakeholders, after which the guidelines were further reviewed and modified. RESULTS: CR involves a more cost-effective use of healthcare resources relative to that of general treatments, and the exercise component of CR lowers cardiovascular mortality and readmission rates, regardless of the type of coronary heart disease and type and setting of CR. CONCLUSION: Individualized CR programs should be considered together with various factors, including differences in heart function and lifestyle, and doing so will boost participation and adherence with the CR program, ultimately meeting the final goals of the program, namely reducing the recurrence of myocardial infarction and mortality rates.
Acute Coronary Syndrome
;
Cardiovascular Diseases
;
Cause of Death
;
Consultants
;
Coronary Disease
;
Delivery of Health Care
;
Heart
;
Hospitals, General
;
Hospitals, University
;
Humans
;
Insurance Benefits
;
Korea
;
Life Style
;
Methods
;
Mortality
;
Myocardial Infarction
;
Nutritionists
;
Physical Therapists
;
Preventive Medicine
;
Recurrence
;
Rehabilitation
;
Secondary Prevention
;
Specialization
;
Sports Medicine
;
Surgeons
6.Clinical Practice Guideline for Cardiac Rehabilitation in Korea Online only
Chul KIM ; Jidong SUNG ; Jong Hwa LEE ; Won Seok KIM ; Goo Joo LEE ; Sungju JEE ; Il Young JUNG ; Ueon Woo RAH ; Byung Ok KIM ; Kyoung Hyo CHOI ; Bum Sun KWON ; Seung Don YOO ; Heui Je BANG ; Hyung Ik SHIN ; Yong Wook KIM ; Heeyoune JUNG ; Eung Ju KIM ; Jung Hwan LEE ; In Hyun JUNG ; Jae Seung JUNG ; Jong Young LEE ; Jae Young HAN ; Eun Young HAN ; Yu Hui WON ; Woosik HAN ; Sora BAEK ; Kyung Lim JOA ; Sook Joung LEE ; Ae Ryoung KIM ; So Young LEE ; Jihee KIM ; Hee Eun CHOI ; Byeong Ju LEE ; Soon KIM
Annals of Rehabilitation Medicine 2019;43(3):355-356
OBJECTIVE: Though clinical practice guidelines (CPGs) for cardiac rehabilitation (CR) are an effective and widely used treatment method worldwide, they are as yet not widely accepted in Korea. Given that cardiovascular disease is the second leading cause of death in Korea, it is urgent that CR programs be developed. In 2008, the Government of Korea implemented CR programs at 11 university hospitals as part of its Regional Cardio-Cerebrovascular Center Project, and three additional medical facilities will be added in 2019. In addition, owing to the promotion of CR nationwide and the introduction of CR insurance benefits, 40 medical institutions nationwide have begun CR programs even as a growing number of medical institutions are preparing to offer CR. The purpose of this research was to develop evidence-based CPGs to support CR implementation in Korea. METHODS: This study is based on an analysis of CPGs elsewhere in the world, an extensive literature search, a systematic analysis of multiple randomized control trials, and a CPG management, development, and assessment committee comprised of 33 authors—primarily rehabilitation specialists, cardiologists, and thoracic surgeons in 21 university hospitals and two general hospitals. Twelve consultants, primarily rehabilitation, sports medicine, and preventive medicine specialists, CPG experts, nurses, physical therapists, clinical nutritionists, and library and information experts participated in the research and development of these CPGs. After the draft guidelines were developed, three rounds of public hearings were held with staff members from relevant academic societies and stakeholders, after which the guidelines were further reviewed and modified. PRINCIPAL CONCLUSIONS: CR involves a more cost-effective use of healthcare resources relative to that of general treatments, and the exercise component of CR lowers cardiovascular mortality and readmission rates, regardless of the type of coronary heart disease and type and setting of CR. Individualized CR programs should be considered together with various factors, including differences in heart function and lifestyle, and doing so will boost participation and adherence with the CR program, ultimately meeting the final goals of the program, namely reducing the recurrence of myocardial infarction and mortality rates.
Acute Coronary Syndrome
;
Cardiovascular Diseases
;
Cause of Death
;
Consultants
;
Coronary Disease
;
Delivery of Health Care
;
Heart
;
Hospitals, General
;
Hospitals, University
;
Humans
;
Insurance Benefits
;
Korea
;
Life Style
;
Methods
;
Mortality
;
Myocardial Infarction
;
Nutritionists
;
Physical Therapists
;
Preventive Medicine
;
Recurrence
;
Rehabilitation
;
Secondary Prevention
;
Specialization
;
Sports Medicine
;
Surgeons
7.Clinical Practice Guideline for Cardiac Rehabilitation in Korea
Chul KIM ; Jidong SUNG ; Jong Hwa LEE ; Won Seok KIM ; Goo Joo LEE ; Sungju JEE ; Il Young JUNG ; Ueon Woo RAH ; Byung Ok KIM ; Kyoung Hyo CHOI ; Bum Sun KWON ; Seung Don YOO ; Heui Je BANG ; Hyung Ik SHIN ; Yong Wook KIM ; Heeyoune JUNG ; Eung Ju KIM ; Jung Hwan LEE ; In Hyun JUNG ; Jae Seung JUNG ; Jong Young LEE ; Jae Young HAN ; Eun Young HAN ; Yu Hui WON ; Woosik HAN ; Sora BAEK ; Kyung Lim JOA ; Sook Joung LEE ; Ae Ryoung KIM ; So Young LEE ; Jihee KIM ; Hee Eun CHOI ; Byeong Ju LEE ; Soon KIM
The Korean Journal of Thoracic and Cardiovascular Surgery 2019;52(4):248-285
BACKGROUND:
Though clinical practice guidelines (CPGs) for cardiac rehabilitation (CR) are an effective and widely used treatment method worldwide, they are as yet not widely accepted in Korea. Given that cardiovascular disease is the second leading cause of death in Korea, it is urgent that CR programs be developed. In 2008, the Government of Korea implemented CR programs at 11 university hospitals as part of its Regional Cardio-Cerebrovascular Center Project, and 3 additional medical facilities will be added in 2019. In addition, owing to the promotion of CR nationwide and the introduction of CR insurance benefits, 40 medical institutions nationwide have begun CR programs even as a growing number of medical institutions are preparing to offer CR. The purpose of this research was to develop evidence-based CPGs to support CR implementation in Korea.
METHODS:
This study is based on an analysis of CPGs elsewhere in the world, an extensive literature search, a systematic analysis of multiple randomized control trials, and a CPG management, development, and assessment committee comprised of 33 authors—primarily rehabilitation specialists, cardiologists, and thoracic surgeons in 21 university hospitals and 2 general hospitals. Twelve consultants, primarily rehabilitation, sports medicine, and preventive medicine specialists, CPG experts, nurses, physical therapists, clinical nutritionists, and library and information experts participated in the research and development of these CPGs. After the draft guidelines were developed, 3 rounds of public hearings were held with staff members from relevant academic societies and stakeholders, after which the guidelines were further reviewed and modified.
RESULTS:
CR involves a more cost-effective use of healthcare resources relative to that of general treatments, and the exercise component of CR lowers cardiovascular mortality and readmission rates, regardless of the type of coronary heart disease and type and setting of CR.
CONCLUSION
Individualized CR programs should be considered together with various factors, including differences in heart function and lifestyle, and doing so will boost participation and adherence with the CR program, ultimately meeting the final goals of the program, namely reducing the recurrence of myocardial infarction and mortality rates.
8.Clinical Practice Guideline for Cardiac Rehabilitation in Korea: Recommendations for Cardiac Rehabilitation and Secondary Prevention after Acute Coronary Syndrome
Chul KIM ; Jidong SUNG ; Jong Hwa LEE ; Won Seok KIM ; Goo Joo LEE ; Sungju JEE ; Il Young JUNG ; Ueon Woo RAH ; Byung Ok KIM ; Kyoung Hyo CHOI ; Bum Sun KWON ; Seung Don YOO ; Heui Je BANG ; Hyung Ik SHIN ; Yong Wook KIM ; Heeyoune JUNG ; Eung Ju KIM ; Jung Hwan LEE ; In Hyun JUNG ; Jae Seung JUNG ; Jong Young LEE ; Jae Young HAN ; Eun Young HAN ; Yu Hui WON ; Woosik HAN ; Sora BAEK ; Kyung Lim JOA ; Sook Joung LEE ; Ae Ryoung KIM ; So Young LEE ; Jihee KIM ; Hee Eun CHOI ; Byeong Ju LEE ; Soon KIM
Korean Circulation Journal 2019;49(11):1066-1111
Though clinical practice guidelines (CPGs) for cardiac rehabilitation (CR) are an effective and widely used treatment method worldwide, they are as yet not widely accepted in Korea. Given that cardiovascular (CV) disease is the second leading cause of death in Korea, it is urgent that CR programs be developed. In 2008, the Government of Korea implemented CR programs at 11 university hospitals as part of its Regional Cardio-Cerebrovascular Center Project, and 3 additional medical facilities will be added in 2019. In addition, owing to the promotion of CR nationwide and the introduction of CR insurance benefits, 40 medical institutions nationwide have begun CR programs even as a growing number of medical institutions are preparing to offer CR. The purpose of this research was to develop evidence-based CPGs to support CR implementation in Korea. This study is based on an analysis of CPGs elsewhere in the world, an extensive literature search, a systematic analysis of multiple randomized control trials, and a CPG management, development, and assessment committee comprised of thirty-three authors—primarily rehabilitation specialists, cardiologists, and thoracic surgeons in 21 university hospitals and 2 general hospitals. Twelve consultants, primarily rehabilitation, sports medicine, and preventive medicine specialists, CPG experts, nurses, physical therapists, clinical nutritionists, and library and information experts participated in the research and development of these CPGs. After the draft guidelines were developed, 3 rounds of public hearings were held with staff members from relevant academic societies and stakeholders, after which the guidelines were further reviewed and modified. CR involves a more cost-effective use of healthcare resources relative to that of general treatments, and the exercise component of CR lowers CV mortality and readmission rates, regardless of the type of coronary heart disease and type and setting of CR. Individualized CR programs should be considered together with various factors, including differences in heart function and lifestyle, and doing so will boost participation and adherence with the CR program, ultimately meeting the final goals of the program, namely reducing the recurrence of myocardial infarction and mortality rates.
9.Association of serum mineral parameters with mortality in hemodialysis patients: Data from the Korean end-stage renal disease registry.
Yunmi KIM ; Kyung Don YOO ; Hyo Jin KIM ; Junga KOH ; Yeonsil YU ; Young Joo KWON ; Gheun Ho KIM ; Tae Hyun YOO ; Joongyub LEE ; Dong Chan JIN ; Bum Soon CHOI ; Yeong Hoon KIM ; Kook Hwan OH
Kidney Research and Clinical Practice 2018;37(3):266-276
BACKGROUND: We investigated the associations between mineral metabolism parameters and mortality to identify optimal targets in Korean hemodialysis patients. METHODS: Among hemodialysis patients registered in the end-stage renal disease registry of the Korean Society of Nephrology between March 2012 and June 2017, those with serum calcium, phosphorus, and intact parathyroid hormone (iPTH) measured at enrollment were included. Association of serum levels of calcium, phosphorus, and iPTH with all-cause mortality was analyzed. RESULTS: Among 21,433 enrolled patients, 3,135 (14.6%) died during 24.8 ± 14.5 months of follow-up. After multivariable adjustment, patients in the first quintile of corrected calcium were associated with lower mortality (hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.71–0.99; P = 0.003), while those in the fifth quintile were associated with higher mortality (HR, 1.39; 95% CI, 1.20–1.61; P < 0.001) compared with those in the third quintile. For phosphorus, only the lowest quintile was significantly associated with increased mortality (HR, 1.24; 95% CI, 1.08–1.43; P = 0.003). The lowest (HR, 1.18; 95% CI, 1.02–1.36; P = 0.026) and highest quintiles of iPTH (HR, 1.24; 95% CI, 1.05–1.46; P = 0.013) were associated with increased mortality. For target counts achieved according to the Kidney Disease Outcomes Quality Initiative guideline, patients who did not achieve any mineral parameter targets hadhigher mortality than those who achieved all three targets (HR, 1.37; 95% CI, 1.12–1.67; P = 0.003). CONCLUSION: In Korean hemodialysis patients, high serum calcium, low phosphorus, and high and low iPTH levels were associated with increased all-cause mortality.
Calcium
;
Follow-Up Studies
;
Humans
;
Kidney Diseases
;
Kidney Failure, Chronic*
;
Metabolism
;
Miners*
;
Mortality*
;
Nephrology
;
Parathyroid Hormone
;
Phosphorus
;
Renal Dialysis*
10.Hepatocyte toll-like receptor 4 mediates lipopolysaccharide-induced hepcidin expression.
Yong Soo LEE ; Yong Hoon KIM ; Yoon Seok JUNG ; Ki Sun KIM ; Don Kyu KIM ; Soon Young NA ; Ji Min LEE ; Chul Ho LEE ; Hueng Sik CHOI
Experimental & Molecular Medicine 2017;49(12):e408-
Hepcidin expression is induced by inflammatory molecules such as lipopolysaccharide (LPS) via a macrophage-mediated pathway. Although hepatocytes directly respond to LPS, the molecular mechanism underlying toll-like receptor (TLR)-dependent hepcidin expression by hepatocytes is mostly unknown. Here we show that LPS can directly induce the mRNA expression and secretion of hepcidin by hepatocytes via TLR4 activation. Using hepatocytes deficient in TLR4, myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor inducing interferon-β (TRIF), we demonstrated that LPS-induced hepcidin expression by hepatocytes is regulated by its specific receptor, TLR4, via a MyD88-dependent signaling pathway. Hepcidin promoter activity was significantly increased by MyD88-dependent downstream signaling molecules (interleukin-1 receptor-associated kinase (IRAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which activate c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1). We then confirmed that LPS stimulation induced the phosphorylation of JNK and c-Jun, and observed strong occupancy of the hepcidin promoter by c-Jun. Promoter mutation analysis also identified the AP-1-binding site on the hepcidin promoter. Finally, bone marrow transplantation between wild-type and TLR4 knockout mice revealed that hepatic TLR4-dependent hepcidin expression was comparable to macrophage TLR4-dependent hepcidin expression induced by LPS. Taken together, these results suggest that TLR4 expressed by hepatocytes regulates hepcidin expression via the IRAK–TRAF6–JNK–AP-1 axis.

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