Publications by authors named "Ha Il Kim"

34 Publications

Cervicocerebral atherosclerosis and its hepatic and coronary risk factors in patients with liver cirrhosis.

Clin Mol Hepatol 2021 Oct 12. Epub 2021 Oct 12.

Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background/aims: This study aimed to investigate the silent atherosclerotic burden of cervicocephalic vessels in cirrhotic patients compared with the general population, and the relevant risk factors including coronary parameters.

Methods: The study population consisted of 993 stroke-free subjects with LC who were screened by magnetic resonance angiography (MRA) of the head and neck as a pre-liver transplant workup, and 6,099 health checkup participants who underwent MRA examination. The two cohorts were matched for cerebrovascular risk factors, and the prevalence rates of atherosclerosis in the major intracranial and extracranial arteries were compared in 755 matched pairs. Also, traditional, hepatic and coronary variables related to the cerebral atherosclerosis were assessed in cirrhotics.

Results: Overall, intracranial atherosclerosis was significantly less prevalent in the LC samples than the matched controls (2.3% vs. 5.4%; P=0.002), whereas the prevalence of extracranial atherosclerosis were similar (4.4% vs. 5.8%; P=0.242). These results were maintained in multivariate analyses in the pooled samples, with the corresponding adjusted odds ratios (ORs) for LC of 0.56 and 0.77 (95% CIs, 0.36-0.88 and 0.55-1.09), respectively. In the cirrhotic series, lower platelet count was inversely correlated with intracranial atherosclerosis (adjusted OR, 0.31; 95% CI, 0.13-0.76). Coronary artery calcium (CAC) score ≥100 was the only factor predicting both intra- and extra-cranial atherosclerosis (adjusted ORs, 4.06 and 5.43; 95% CIs, 1.45-11.41 and 2.68-11.00, respectively).

Conclusions: Our data suggest that LC confers protection against intracranial atherosclerosis, and that thrombocytopenia may be involved in this protection. High CAC score could serve as a potential surrogate for cervicocerebral vascular screening in asymptomatic cirrhotics.
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http://dx.doi.org/10.3350/cmh.2021.0202DOI Listing
October 2021

Integrated prognostic and histogenomic justification of stage-directed therapy for single large hepatocellular carcinoma: a Korean nationwide registry study.

Gut 2021 Sep 7. Epub 2021 Sep 7.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, The Republic of Korea

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http://dx.doi.org/10.1136/gutjnl-2021-325844DOI Listing
September 2021

Role of the alpha-fetoprotein response in immune checkpoint inhibitor-based treatment of patients with hepatocellular carcinoma.

J Cancer Res Clin Oncol 2021 Aug 30. Epub 2021 Aug 30.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.

Purpose: The dynamics of serum alpha-fetoprotein (AFP) level have been found to be a useful predictor of therapeutic responsiveness in patients with hepatocellular carcinoma (HCC). We evaluated whether AFP changes were able to accurately reflect imaging-based responses and predict prognosis in patients receiving therapies including immune-checkpoint inhibitors (ICIs).

Methods: A total of 108 HCC patients with baseline serum AFP ≥ 20 ng/mL who received ICI-based treatment were included. We evaluated AFP-based responses, coupled with radiographic responses by RECIST, at 6-10 (time-point 1, TP1) and 14-18 weeks (time-point 2, TP2) of therapy in terms of the change of AFP from baseline, with a > 20% decrease or increase in level corresponding to the AFP response and progression, respectively. We examined the correlations between AFP and imaging-based responses, and the prognostic implications of the AFP-based measure.

Results: Based on AFP change, there were 24 and 20 responders and 74 and 24 progressors at TP1 and TP2, respectively. The AFP responders yielded radiological objective responses in 90.9% (10/11) and 93.8% (15/16) of the cases at TP1 and TP2, respectively, compared with only 1.4% and none, respectively, of the AFP progressors at the corresponding times. The agreement between progression by RECIST and increased AFP level at the two time-points was 93.8% and 95.0%, respectively. The accuracy of the AFP-based criterion for predicting radiologic response/progression was comparable at TP1 and TP2. Both "AFP responder" and "AFP progressor" at TP1 or TP2 independently predicted the overall survival of patients (adjusted hazard ratios [95% confidence intervals], 0.360 [0.174-0.743] and 0.315 [0.117-0.850]; and 2.525 [1.362-4.679] and 3.908 [1.563-9.769], respectively).

Conclusion: Our study suggests that on-treatment AFP changes can complement imaging findings and provide prognostic information for evaluating patients with AFP-producing HCC treated with ICI-based regimens.
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http://dx.doi.org/10.1007/s00432-021-03727-yDOI Listing
August 2021

Seasonal variations in the diagnosis of the top 10 cancers in Korea: A nationwide population-based study using a common data model.

J Gastroenterol Hepatol 2021 Jul 22. Epub 2021 Jul 22.

Department of Internal Medicine, Division of Gastroenterology, Kyung Hee University School of Medicine, Seoul, Korea.

Background And Aim: A better understanding of seasonal variations in cancer diagnosis may be the first step toward optimal resource distribution in the National Cancer Screening Program (NCSP). This study aimed to identify seasonal variations in the diagnosis of the top 10 major cancers in Korea.

Methods: We conducted a retrospective, observational cohort study in participants aged ≥ 20 years between 2012 and 2016 from the Health Insurance Review and Assessment-National Patient Sample database, previously converted to a common data model. We assessed the overall seasonal variations in the 10 major cancers.

Results: We analyzed the following top 10 cancers: stomach (n = 3435), colorectal (n = 5368), liver (n = 7605), pancreatic (n = 2946), gallbladder (n = 899), lung (n = 1598), prostate (n = 2897), thyroid (n = 1966), breast (n = 1313), and kidney (n = 668) cancers. All cancers showed similar seasonal variations in diagnosis, with a significant winter peak. A winter peak in diagnosis was observed for NCSP-covered cancers, such as stomach, colon, liver, and breast cancers, as well as other cancers not covered by the NCSP. The winter peak for cancer diagnosis was the highest for breast cancer (74.4%) followed by thyroid (51.0%) and stomach cancers, whereas it was the lowest for pancreatic cancer followed by prostate and colorectal cancers.

Conclusions: Significant seasonal variations were found in the diagnosis of the top 10 major cancers, with a winter peak, which may be explained by the participants' behavior pattern with respect to the NCSP. Our findings suggest that trading off of NCSP healthcare resources between winter and other seasons may be beneficial.
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http://dx.doi.org/10.1111/jgh.15634DOI Listing
July 2021

Seasonal variation of peptic ulcer disease, peptic ulcer bleeding, and acute pancreatitis: A nationwide population-based study using a common data model.

Medicine (Baltimore) 2021 May;100(21):e25820

Department of Internal Medicine, Division of Gastroenterology, Kyung Hee University Hospital at Gang Dong, Seoul, Republic of Korea.

Abstract: Although gastrointestinal diseases are reported at various times throughout the year, some particular seasons are associated with a higher incidence of these diseases. This study aimed to identify the seasonal variations of peptic ulcer (PU), peptic ulcer bleeding (PUB), and acute pancreatitis (AP) in South Korea.We conducted a retrospective, observational cohort study of all subjects aged >18 years between 2012 and 2016 using the Health Insurance Review and Assessment-National Patient Samples database, previously converted to the standardized Observational Medical Outcomes Partnership-Common Data Model. We assessed the overall seasonal variations of PU, PUB, and AP and further analyzed seasonal variations according to age and sex subgroups.In total, 14,626 patients with PU, 3575 with PUB, and 9023 with AP were analyzed for 5 years. A clear seasonal variation was noted in PU, with the highest incidence rate during winter, the second highest during spring, the third highest during summer, and the lowest incidence during autumn for 5 years (P < .001). PUB also showed significant seasonal fluctuations, with winter peak for 4 years, except 1 year, which had a spring peak (P < .001). However, AP showed no clear seasonal variations (P = .090). No significant differences in the seasonal variation of PU, PUB, and AP were observed according to sex and age subgroups (<60 years vs ≥60 years).Seasonal variation of PU and PUB should be considered when determining allocation of available health care resources.
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http://dx.doi.org/10.1097/MD.0000000000025820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154390PMC
May 2021

Incidence and management patterns of alcohol-related liver disease in Korea: a nationwide standard cohort study.

Sci Rep 2021 03 23;11(1):6648. Epub 2021 Mar 23.

Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, 05278, Korea.

The recent incidence and management patterns of alcohol-related liver disease (ARLD) are not well defined in Korea. We sought to evaluate the epidemiology of ARLD with regard to disease severity and alcohol cessation management after diagnosis. We performed an observational cohort study of standardized Common Data Model data from the Health Insurance Review and Assessment-National Patient Samples database between 2012 and 2016. The incidence and demographic properties of ARLD were extracted and divided into non-cirrhotic alcoholic liver disease (ALD) and alcoholic liver cirrhosis (ALC). ALC was compared with non-alcoholic cirrhosis by severity at diagnosis. The management patterns were captured by the initiation of pharmaco- and behavioral therapy for alcohol cessation. We analyzed data from 72,556 ALD to 7295 ALC patients. The ALD incidence was stable from 990 to 1025 per 100,000 people. In ALD, the proportion of patients who were ≥ 65 years old, the proportion of female patients, and the comorbidity index increased significantly during the study period (all P values < 0.001). ALC accounted for > 20% of all cirrhosis, with decompensation occurring twice as often as in non-alcoholic cirrhosis. The initiation of alcoholism management was stationary in ARLD, remaining at < 10% for both pharmacotherapy and behavioral therapy, regardless of severity or the site of diagnosis. The incidence of ARLD did not decrease during the study period. Moreover, an increasing trend in the proportion of people vulnerable to drinking was observed. Unfortunately, management for the cessation of alcohol use remains very low. The best way to manage ARLD should be evaluated in further study.
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http://dx.doi.org/10.1038/s41598-021-86197-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987970PMC
March 2021

Deep Convolutional Neural Network-Based Lymph Node Metastasis Prediction for Colon Cancer Using Histopathological Images.

Front Oncol 2020 13;10:619803. Epub 2021 Jan 13.

Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, South Korea.

Background: Human evaluation of pathological slides cannot accurately predict lymph node metastasis (LNM), although accurate prediction is essential to determine treatment and follow-up strategies for colon cancer. We aimed to develop accurate histopathological features for LNM in colon cancer.

Methods: We developed a deep convolutional neural network model to distinguish the cancer tissue component of colon cancer using data from the tissue bank of the National Center for Tumor Diseases and the pathology archive at the University Medical Center Mannheim, Germany. This model was applied to whole-slide pathological images of colon cancer patients from The Cancer Genome Atlas (TCGA). The predictive value of the peri-tumoral stroma (PTS) score for LNM was assessed.

Results: A total of 164 patients with stages I, II, and III colon cancer from TCGA were analyzed. The mean PTS score was 0.380 (± SD = 0.285), and significantly higher PTS scores were observed in patients in the LNM-positive group than those in the LNM-negative group ( < 0.001). In the univariate analyses, the PTS scores for the LNM-positive group were significantly higher than those for the LNM-negative group ( < 0.001). Further, the PTS scores in lymphatic invasion and any one of perineural, lymphatic, or venous invasion were significantly increased in the LNM-positive group ( < 0.001 and < 0.001).

Conclusion: We established the PTS score, a simplified reproducible parameter, for predicting LNM in colon cancer using computer-based analysis that could be used to guide treatment decisions. These findings warrant further confirmation through large-scale prospective clinical trials.
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http://dx.doi.org/10.3389/fonc.2020.619803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838556PMC
January 2021

Gastrointestinal and Nongastrointestinal Complications of Esophagogastroduodenoscopy and Colonoscopy in the Real World: A Nationwide Standard Cohort Using the Common Data Model Database.

Gut Liver 2021 07;15(4):569-578

Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea.

Background/aims: The global trend of an expanding aged population has increased concerns about complications correlated with gastrointestinal (GI) endoscopy in elderly patients; however, there have been few reports published on this issue.

Methods: In this retrospective, observational cohort study performed between 2012 and 2017, serious complications of esophagogastroduodenoscopy (EGD), colonoscopy, and colonoscopic polypectomy were compared between patients according to age (≥65 years vs 18-64 years). We used the Health Insurance Review and Assessment-National Patient Samples database, previously converted to the standardized Observational Medical Outcomes Partnership-Common Data Model. Serious complications within 30 days of the procedure included both GI complications (bleeding and perforation) and non-GI complications (cerebrovascular accident [CVA], acute myocardial infarction [AMI], congestive heart failure [CHF], and death).

Results: A total of 387,647 patients who underwent EGD, 241,094 who underwent colonoscopy, and 89,059 who underwent colonoscopic polypectomy were assessed as part of this investigation. During the study period, endoscopic procedures in the older group steadily increased in number in all endoscopy groups (all p<0.001). Further, pooled complication rates of bleeding, CVA, AMI, CHF, and death were approximately three times higher among older patients who underwent EGD or colonoscopy. Moreover, pooled complication rates of CVA, AMI, CHF, and death were approximately 2.2 to 5.0 times higher among older patients who underwent colonoscopic polypectomy.

Conclusions: Elderly patients experienced approximately three times more GI and non-GI complications after EGD or colonoscopy than young patients. Physicians should pay attention to the potential risks of GI endoscopy in elderly patients.
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http://dx.doi.org/10.5009/gnl20222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283291PMC
July 2021

Variceal bleeding is aggravated by portal venous invasion of hepatocellular carcinoma: a matched nested case-control study.

BMC Cancer 2021 Jan 5;21(1):11. Epub 2021 Jan 5.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.

Background: We hypothesized that portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) increases portal pressure and causes esophageal varices and variceal bleedings. We examined the incidence of high-risk varices and variceal bleeding and determined the indications for variceal screening and prophylaxis.

Methods: This study included 1709 asymptomatic patients without any prior history of variceal hemorrhage or endoscopic prophylaxis who underwent upper endoscopy within 30 days before or after initial anti-HCC treatment. Of these patients, 206 had PVTT, and after 1:2 individual matching, 161 of them were matched with 309 patients without PVTT. High-risk varices were defined as large/medium varices or small varices with red-color signs and variceal bleeding. Bleeding rates from the varices were compared between matched pairs. Risk factors for variceal bleeding in the entire set of patients with PVTT were also explored.

Results: In the matched-pair analysis, the proportion of high-risk varices at screening (23.0% vs. 13.3%; P = 0.003) and the cumulative rate of variceal bleeding (4.5% vs. 0.4% at 1 year; P = 0.009) were significantly greater in the PVTT group. Prolonged prothrombin time, lower platelet count, presence of extrahepatic metastasis, and Vp4 PVTT were independent risk factors related to high-risk varices in the total set of 206 patients with PVTT (Adjusted odds ratios [95% CIs], 1.662 [1.151-2.401]; 0.985 [0.978-0.993]; 4.240 [1.783-10.084]; and 3.345 [1.457-7.680], respectively; Ps < 0.05). During a median follow-up of 43.2 months, 10 patients with PVTT experienced variceal bleeding episodes, 9 of whom (90%) had high-risk varices. Presence of high-risk varices and sorafenib use for HCC treatment were significant predictors of variceal bleeding in the complete set of patients with PVTT (Adjusted hazard ratios [95% CIs], 26.432 [3.230-216.289]; and 5.676 [1.273-25.300], respectively; Ps < 0.05).

Conclusions: PVTT in HCC appears to increase the likelihood of high-risk varices and variceal bleeding. In HCC patients with PVTT, endoscopic prevention could be considered, at least in high-risk variceal carriers taking sorafenib.
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http://dx.doi.org/10.1186/s12885-020-07708-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786454PMC
January 2021

Fatal Necrotizing Fasciitis Following Uncomplicated Colonoscopic Polypectomy: A Case Report.

Clin Endosc 2021 Mar 11;54(2):280-284. Epub 2020 Dec 11.

Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea.

Necrotizing fasciitis (NF) is a life-threatening infection that can be caused by various procedures or surgery and may develop in healthy elderly patients. Here, we report a case of a 66-year-old man with diabetes mellitus who underwent colonoscopic polypectomy, without complications. However, he visited the emergency department 24 hours after the procedure complaining of abdominal pain. Abdominopelvic computed tomography revealed multiple air bubbles in the right lateral abdominal muscles. After a diagnosis of NF was made, immediate surgical debridement was performed. However, despite three sessions of extensive surgical debridement and best supportive care at the intensive care unit, the patient died because of sepsis and NF-associated multiple-organ failure. In conclusion, physicians should pay special attention to the possibility of NF if a patient with risk factors for NF develops sepsis after colonoscopic polypectomy.
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http://dx.doi.org/10.5946/ce.2020.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039750PMC
March 2021

Polydeoxyribonucleotide Exerts Protective Effect Against CCl-Induced Acute Liver Injury Through Inactivation of NF-κB/MAPK Signaling Pathway in Mice.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul 05278, Korea.

Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect of PDRN against carbon tetrachloride (CCl)-induced ALI was investigated using mice. For the induction of ALI, mice received intraperitoneal injection of CCl twice over seven days. Mice from the PDRN-treated groups received an intraperitoneal injection of 200 μL saline containing PDRN (8 mg/kg), once a day for seven days, starting on day 1 after the first CCl injection. In order to confirm that the action of PDRN occurs through the adenosine A receptor, 8 mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine A receptor antagonist, was treated with PDRN. Administration of CCl impaired liver tissue and increased the liver index and histopathologic score. The expression of pro-inflammatory cytokines was increased, and apoptosis was induced by the administration of CCl. Administration of CCl activated nuclear factor-kappa B (NF-κB) and facilitated phosphorylation of signaling factors in mitogen-activated protein kinase (MAPK). In contrast, PDRN treatment suppressed the secretion of pro-inflammatory cytokines and inhibited apoptosis. PDRN treatment inactivated NF-κB and suppressed phosphorylation of signaling factors in MAPK. As a result, liver index and histopathologic score were reduced by PDRN treatment. When PDRN was treated with DMPX, the anti-inflammatory and anti-apoptotic effect of PDRN disappeared. Therefore, PDRN can be used as an effective therapeutic agent for acute liver damage.
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http://dx.doi.org/10.3390/ijms21217894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660684PMC
October 2020

Continued value of the serum alpha-fetoprotein test in surveilling at-risk populations for hepatocellular carcinoma.

PLoS One 2020 26;15(8):e0238078. Epub 2020 Aug 26.

Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Backgrounds And Aims: Because of the known limitations of ultrasonography (US) alone, we re-evaluated whether complimentary testing for serum alpha-fetoprotein (AFP) is helpful in surveilling for hepatocellular carcinoma (HCC) in high-risk populations.

Methods: We included, from a hospital-based cancer registry, 1,776 asymptomatic adults who were surveilled biannually with the AFP test and US and eventually diagnosed with HCC between 2007 and 2015. Based on the screening results, these patients were divided into three groups: AFP (positive for AFP only; n = 298 [16.8%]), US (positive for US only; n = 978 [55.0%]), and AFP+US (positive for both; n = 500 [28.2%]). We compared the outcomes of the three groups, calculating the survival of the AFP group both as observed survival and as survival corrected for lead-time.

Results: In terms of tumor-related factors, the separate AFP and US groups were more likely to have early stage HCC and to receive curative treatments than the combined AFP+US group (Ps<0.05). The AFP group had significantly better overall and cancer-specific survival than the AFP+US group after adjusting for covariates (adjusted hazard ratios [HRs] 0.68 and 0.62, respectively). In analyses correcting for lead-time in the AFP group (doubling time 120 days), the respective adjusted HRs for the AFP group were unchanged (0.74 and 0.67), but they were no longer significant after additional adjustment for tumor stage and curative treatment (0.87 and 0.81).

Conclusions: HCC cases detected by the AFP test without abnormal ultrasonic findings appear to have better survival, possibly as a result of stage migration and the resulting cures. Complementary AFP surveillance, together with US, could be helpful for at-risk patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449471PMC
October 2020

Real-World Use of Colonoscopy in an Older Population: A Nationwide Standard Cohort Study Using a Common Data Model.

Dig Dis Sci 2021 07 20;66(7):2227-2234. Epub 2020 Jul 20.

Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea.

Backgrounds And Aims: Rapid population aging is considered to be a major factor in increased colonoscopy use in Korea. However, real-world use of colonoscopy in older populations is rarely evaluated using Korean databases.

Methods: We conducted a retrospective, observational cohort study of individuals aged over 20 years between 2012 and 2017. We used the Health Insurance Review and Assessment-National Patient Samples database, previously converted to the standardized Observational Medical Outcomes Partnership-Common Data Model. The use of diagnostic colonoscopy and colonoscopic polypectomy was evaluated, stratified by age group and sex.

Results: During the study period, we captured data from the database on 240,406 patients who underwent diagnostic colonoscopy and 88,984 who underwent colonoscopic polypectomy. During the study period, use of diagnostic colonoscopy and colonoscopic polypectomy steadily increased, but both procedures were most significantly increased in the 65- to 85-year group compared to other age groups (p < 0.05). Average ages for both procedures significantly increased in the most recent 3 years (p < 0.05). Polypectomy rates for men plateaued in the 50- to 64-year age group, but rates for women steadily increased up to the 65- to 85-year group. Polypectomy rates were higher for men than for women in all index years.

Conclusions: The use of diagnostic colonoscopy and colonoscopic polypectomy significantly increased in the 65- to 85-year age group. Our findings suggest that more available colonoscopy resources should be allocated to older populations, considering the aging society in Asian countries.
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http://dx.doi.org/10.1007/s10620-020-06494-xDOI Listing
July 2021

Hepatocyte-Specific Magnetic Resonance Imaging-Based Assessment of Indeterminate Hepatic Nodules in the Liver Transplant Evaluation of Patients With Cirrhosis.

Liver Transpl 2020 03;26(3):359-369

Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea.

We aimed to determine the identities in explants of indeterminate hepatic nodules (IDNs) that had been scanned by dynamic magnetic resonance imaging (MRI) to establish clinicoradiological parameters predicting which IDNs were hepatocellular carcinomas (HCCs). This study included 88 patients with cirrhosis who underwent gadoxetic acid-enhanced MRI in pre-liver transplantation (LT) workup followed within 90 days by primary LT. The MRI detected 168 hepatic nodules that were classified into 6 benign tumors, 49 HCCs, and 113 IDNs, in 5, 34, and 72 patients, respectively. We compared these pre-LT radiologic diagnoses and stagings with explant pathology on a per-lesion basis to enable us to identify features of IDNs related to malignancy. Of the 168 nodules seen on MRI, 119 that were classified radiologically as consisting of 1 benign nodule (33.3%), 46 HCCs (93.9%), and 72 IDNs (63.7%) all turned out to be pathological HCCs. Of 32 patients inside Milan and 54 without HCC staged by MRI, 11 progressed beyond the criteria after LT. High serum alpha-fetoprotein level (≥20 ng/mL) was the only per-patient factor significantly associated with malignant IDNs. Per-tumor analysis of the MRI signals revealed that arterial hyperintensity, hepatobiliary hypointensity, T -weighted mild-to-moderate intensity, and restricted diffusion-weighted images were significantly correlated with malignant IDN. A model combining these 4 MRI factors with alpha-fetoprotein level had the best performance in predicting the identification of IDNs as HCCs in explanted livers. Over 60% of the IDNs seen on dynamic images of cirrhotic livers proved to be HCCs when explanted livers were examined. It may therefore be possible to identify HCCs with reasonable accuracy by means of their hepatocyte-specific MRI features when patients are being assessed for LT.
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http://dx.doi.org/10.1002/lt.25684DOI Listing
March 2020

The clinical behavior and survival of patients with hepatocellular carcinoma and a family history of the disease.

Cancer Med 2019 11 18;8(15):6624-6633. Epub 2019 Sep 18.

Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Familial clustering is a common feature of hepatocellular carcinoma (HCC) as well as a risk factor for the disease. We aimed to assess whether such a family history affected prognostic outcomes in patients with HCC diagnosed at different stages of the disease.

Materials/methods: This hospital registry-based cohort study included 5484 patients initially diagnosed with HCC. Individual family histories of cancer were obtained by interview and reported by trained nurses who constructed three-generation pedigrees. Overall survival data were compared between cases with and without first-degree relatives affected by HCC, with adjustment for other potential predictors.

Results: Of 5484 patients, 845 (15.4%) had first-degree relatives with a history of HCC. Family history was associated with longer survival in the entire cohort (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.80-0.98, P = .025). A significant trend for reduced risk of death with increasing number of affected family members was also observed (P for trend = 0.018). The stage-stratified analysis showed that the presence of family history was especially associated with a reduced risk of death in the subset of patients with HCC at a (very) early stage (adjusted HR 0.83, 95% CI 0.69-0.99; P = .042). The proportion of cases receiving curative treatment was also higher in early-stage patients with a family history (72.6% vs 63.3%; P < .001).

Conclusions: A first-degree family history of the disease is a prognostic factor for improved survival in patients with HCC, especially in those whose tumors can be cured by radical treatments.
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http://dx.doi.org/10.1002/cam4.2543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825981PMC
November 2019

A Prospective Evaluation of the Reliability and Utility of Quality of Life Measures in Patients With Hepatocellular Carcinoma.

Am J Clin Oncol 2019 07;42(7):555-563

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul.

Objectives: Little is known about how quality of life (QOL) can assist clinical decision-making for patients with hepatocellular carcinoma (HCC). This study aimed to investigate the reliability and validity of QOL as well as its prognostic value and utility.

Materials And Methods: A prospective cohort of 300 HCC patients at various stages was recruited from 2015 to 2017 in Korea. The subjects answered the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and QLQ-HCC18 and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Prognostic nomograms including the QOL scales were developed. The prediction performance of the Barcelona Clinic Liver Cancer (BCLC) and the American Joint Committee on Cancer (AJCC) staging systems when they were incorporated with QOL was investigated.

Results: The EORTC QLQ-C30 and QLQ-HCC18 subscales showed higher reliability than FACT-Hep subscales. With regard to the validity, both questionnaires discriminated the patients by stages, treatment modalities, and performance status effectively. Multivariable analysis revealed that EORTC role functioning and EORTC appetite loss subscales were statistically associated with overall survival and disease progression. The developed nomograms accurately estimated the 1-year overall survival and disease progression-free rates. Incorporating the EORTC role functioning subscale or Hepatobiliary Cancer Subscale of FACT-Hep with the BCLC and AJCC systems improved the prognostic classification. Incorporating QOL into the AJCC system showed better predictive accuracy than incorporating performance status into it did.

Conclusions: The findings suggest that QOL data can serve as a reliable predictive factor and assist prognostic calculation for HCC patients.
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http://dx.doi.org/10.1097/COC.0000000000000555DOI Listing
July 2019

A case of ulcerative colitis presenting with cerebral venous thrombosis.

Intest Res 2018 Apr 30;16(2):306-311. Epub 2018 Apr 30.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Patients with inflammatory bowel disease (IBD) have been reported to have an increased risk of thromboembolism. Cerebral venous thrombosis (CVT) is a rare but serious extraintestinal manifestation of IBD. Due to its highly variable manifestation and low incidence, CVT is not usually readily recognized by physicians. Herein, we report a case of a 35-year-old male presenting with CVT associated with ulcerative colitis (UC). The patient was admitted with chief complaints of bloody diarrhea that had started 3 days prior. Sigmoidoscopy showed hyperemic and edematous mucosa, friability, and shallow ulcers from the sigmoid colon to the rectum suggestive of IBD. Three days later, the patient started complaining of a headache, and gradually developed a decreased level of consciousness. Magnetic resonance imaging of the brain revealed CVT with hemorrhagic infarctions. An angiogram was obtained to evaluate the extent of CVT, and anticoagulation therapy was initiated with intravenous heparin. During hospitalization, he was diagnosed with UC and treated with 5-aminosalicylic acid. After discharge, the patient was recovered without neurological deficit, and remission of UC was also obtained. The presence of headache or acute worsening of neurological status in a patient with IBD should alert the health professionals about the possibility of CVT.
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http://dx.doi.org/10.5217/ir.2018.16.2.306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934605PMC
April 2018

[Clinical Outcomes of Angiography and Transcatheter Arterial Embolization for Acute Gastrointestinal Bleeding: Analyses according to Bleeding Sites and Embolization Types].

Korean J Gastroenterol 2018 04;71(4):219-228

Division of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background/aims: The clinical outcomes of angiography and transcatheter arterial embolization (TAE) for acute gastrointestinal bleeding (GIB) have not been completely assessed, especially according to bleeding sites. This study aimed to assess the efficacy of angiography and safety of TAE in acute GIB.

Methods: This was a retrospective study evaluating the records of 321 patients with acute GIB who underwent angiography with or without TAE. Targeted TAE was conducted in 134 patients, in whom angiography showed bleeding sources. Prophylactic TAE was performed in 29 patients when the bleeding source was not detected but a specific vessel was strongly suspected by other examinations. The rate of technical success, clinical success, and complications were analyzed.

Results: The detection rate of bleeding source via angiography was 50.8% (163/321), which was not different according to the bleeding sites. The detection rate was higher if the probable bleeding source had already been found by another investigation (59.7% vs. 35.8%, p<0.001). TAE sites were upper GIB in 67, mid GIB in 74, and lower GIB in 22. The technical success rate was 99.3% (133/134), and the clinical success rate was 63.0% (104/163). The prophylactic embolization group showed lower clinical success rate than the targeted embolization group (44.8% vs. 67.9%, p=0.06). The TAE-related complication rate was 12.9% (21/163). Ischemia and/or infarction was more common after TAE for mid and lower GIB than for upper GIB (15.6% vs. 3.0%, p=0.007).

Conclusions: Angiography with or without TAE was an effective method for acute GIB. Targeted embolization should be performed if possible given that it has a higher clinical success rate.
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http://dx.doi.org/10.4166/kjg.2018.71.4.219DOI Listing
April 2018

Gastrocolocutaneous Fistula: An Unusual Case of Gastrostomy Tube Malfunction with Diarrhea.

Clin Endosc 2018 Mar 31;51(2):196-200. Epub 2017 Aug 31.

Division of Gastroenterology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

A gastrocolocutaneous fistula is a rare complication of percutaneous endoscopic gastrostomy (PEG). We report a case of a gastrocolocutaneous fistula presenting with intractable diarrhea and gastrostomy tube malfunction. A 62-year-old woman with a history of multiple system atrophy was referred to us because of PEG tube malfunction. Twenty days prior to presentation, the patient started developing sudden diarrhea within minutes after starting PEG feeding. Fluoroscopy revealed that the balloon of the PEG tube was located in the lumen of the transverse colon with the contrast material filling the colon. Subsequently, the PEG tube was removed and the opening of the gastric site was endoscopically closed using hemoclips. Clinicians should be aware of gastrocolocutaneous fistula as one of the complications of PEG insertion. Sudden onset of diarrhea, immediately after PEG feedings, might suggest this complication, which can be effectively treated with endoscopic closure.
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http://dx.doi.org/10.5946/ce.2017.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903073PMC
March 2018

Transcriptional regulation of glucose sensors in pancreatic beta cells and liver.

Curr Diabetes Rev 2006 Feb;2(1):11-8

Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea.

Derangement of glucose metabolism is a key feature of T2DM, with the liver and pancreatic beta-cells playing a key role in glucose homeostasis. In the postprandial state, glucose is transported into hepatocytes and either metabolized to fatty acids or CO(2), or stored as glycogen. Glucose also acts as a key signal in pancreatic beta-cells for regulating insulin secretion. Because GLUT2 and GK expressed in liver and beta-cells are responsible for sensing glucose levels in the blood, studies on the regulation of these biomolecules are important in understanding glucose homeostasis in vivo. These molecules are known to be regulated either transcriptionally or post-transcriptionally, and recent studies on the structure and function of promoters of these genes have revealed the involvement of various transcriptional factors in their regulation. Here, we review recent progress in elucidating the transcriptional regulation of glucose sensors in the liver and pancreatic beta-cells and the relevance to T2DM.
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http://dx.doi.org/10.2174/157339906775473581DOI Listing
February 2006

The functional relationship between co-repressor N-CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor alpha.

Biochem J 2008 Apr;411(1):19-26

Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, 134 Sinchon-dong, Seodaemun-gu, Seoul 120-752, South Korea.

A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between co-repressors N-CoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). To address the functional relationship between SMRT and N-CoR in TR (thyroid hormone receptor)-mediated repression, we have identified multiple TR target genes, including BCL3 (B-cell lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (beta-adrenergic receptor 2). We demonstrated that siRNA (small interfering RNA) treatment against either N-CoR or SMRT is sufficient for the de-repression of multiple TR target genes. By the combination of sequence mining and physical association as determined by ChIP (chromatin immunoprecipitation) assays, we mapped the putative TREs (thyroid hormone response elements) in BCL3, Spot14, FAS and ADRB2 genes. Our data clearly show that SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking down SMRT. Finally, unliganded, co-repressor-free TR is defective in repression and interacts with a co-activator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes.
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http://dx.doi.org/10.1042/BJ20071393DOI Listing
April 2008

Anti-histone acetyltransferase activity from allspice extracts inhibits androgen receptor-dependent prostate cancer cell growth.

Biosci Biotechnol Biochem 2007 Nov 7;71(11):2712-9. Epub 2007 Nov 7.

Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University.

Histone acetylation depends on the activity of two enzyme families, histone acetyltransferase (HAT) and deacetylase (HDAC). In this study, we screened various plant extracts to find potent HAT inhibitors. Hot water extracts of allspice inhibited HAT activity, especially p300 and CBP (40% at 100 microg/ml). The mRNA levels of two androgen receptor (AR) regulated genes, PSA and TSC22, decreased with allspice treatment (100 microg/ml). Importantly, in IP western analysis, AR acetylation was dramatically decreased by allspice treatment.Furthermore, chromatin immunoprecipitation indicated that the acetylation of histone H3 in the PSA and B2M promoter regions was also repressed. Finally, allspice treatment reduced the growth of human prostate cancer cells, LNCaP (50% growth inhibition at 200 microg/ml). Taken together, our data indicate that the potent HAT inhibitory activity of allspice reduced AR and histone acetylation and led to decreased transcription of AR target genes, resulting in inhibition of prostate cancer cell growth.
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http://dx.doi.org/10.1271/bbb.70306DOI Listing
November 2007

Transcriptional activation of SHP by PPAR-gamma in liver.

Biochem Biophys Res Commun 2007 Aug 6;360(2):301-6. Epub 2007 Jun 6.

Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Republic of Korea.

The mechanism of how PPARgamma decrease gluconeogenic gene expressions in liver is still unclear. Since PPARgamma is a transcriptional activator, it requires a mediator to decrease the transcription of gluconeogenic genes. Recently, SHP has been shown to mediate the bile acid-dependent down regulation of gluconeogenic gene expression in liver. This led us to explore the possibility that SHP may mediate the antigluconeogenic effect of PPARgamma. In the present study, we have identified and characterized the presence of functional PPRE in human SHP promoter. We show the binding of PPARgamma/RXRalpha heterodimer to the PPRE and increased SHP expression by rosiglitazone in primary rat hepatocytes. Taken together with the previous reports about the function of SHP on gluconeogenesis, our results indicate that SHP can mediate the acute antigluconeogenic effect of PPARgamma.
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http://dx.doi.org/10.1016/j.bbrc.2007.05.171DOI Listing
August 2007

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes.

IUBMB Life 2007 Mar;59(3):134-45

Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemoon-gu, Seoul, Korea.

The gene expression of glucose transporter type 4 isoform (GLUT4) is known to be controlled by metabolic, nutritional, or hormonal status. Understanding the molecular mechanisms governing GLUT4 gene expression is critical, because glucose disposal in the body depends on the activities of GLUT4 in the muscle and adipocytes. The GLUT4 activities are regulated by a variety of mechanisms. One of them is transcriptional regulation. GLUT4 gene expression is regulated by a variety of transcriptional factors in muscle and adipose tissue. These data are accumulating regarding the transcriptional factors regulating GLUT4 gene expression. These include MyoD, MEF2A, GEF, TNF-alpha, TR-1alpha, KLF15, SREBP-1c, C/EBP-alpha, O/E-1, free fatty acids, PAPRgamma, LXRalpha, NF-1, etc. These factors are involved in the positive or negative regulation of GLUT4 gene expression. In addition, there is a complex interplay between these factors in transactivating GLUT4 promoter activity. Understanding the mechanisms controlling GLUT4 gene transcription in these tissues will greatly promote the potential therapeutic drug development for obesity and T2DM.
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http://dx.doi.org/10.1080/15216540701313788DOI Listing
March 2007

Regulation of GLUT4 gene expression by SREBP-1c in adipocytes.

Biochem J 2006 Oct;399(1):131-9

Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea.

Expression of the GLUT4 (glucose transporter type 4 isoform) gene in adipocytes is subject to hormonal or metabolic control. In the present study, we have characterized an adipose tissue transcription factor that is influenced by fasting/refeeding regimens and insulin. Northern blotting showed that refeeding increased GLUT4 mRNA levels for 24 h in adipose tissue. Consistent with an increased GLUT4 gene expression, the mRNA levels of SREBP (sterol-regulatory-element-binding protein)-1c in adipose tissue were also increased by refeeding. In streptozotocin-induced diabetic rats, insulin treatment increased the mRNA levels of GLUT4 in adipose tissue. Serial deletion, luciferase reporter assays and electrophoretic mobility-shift assay studies indicated that the putative sterol response element is located in the region between bases -109 and -100 of the human GLUT4 promoter. Transduction of the SREBP-1c dominant negative form to differentiated 3T3-L1 adipocytes caused a reduction in the mRNA levels of GLUT4, suggesting that SREBP-1c mediates the transcription of GLUT4. In vivo chromatin immunoprecipitation revealed that refeeding increased the binding of SREBP-1 to the putative sterol-response element in the GLUT4. Furthermore, treating streptozotocin-induced diabetic rats with insulin restored SREBP-1 binding. In addition, we have identified an Sp1 binding site adjacent to the functional sterol-response element in the GLUT4 promoter. The Sp1 site appears to play an additive role in SREBP-1c mediated GLUT4 gene upregulation. These results suggest that upregulation of GLUT4 gene transcription might be directly mediated by SREBP-1c in adipose tissue.
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http://dx.doi.org/10.1042/BJ20060696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570175PMC
October 2006

Glucose-stimulated upregulation of GLUT2 gene is mediated by sterol response element-binding protein-1c in the hepatocytes.

Diabetes 2005 Jun;54(6):1684-91

Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea.

GLUT2 is mainly expressed in the liver, beta-cells of the pancreas, and the basolateral membrane of kidney proximal tubules and plays an important role in glucose homeostasis in living organisms. The transcription of the GLUT2 gene is known to be upregulated in the liver during postprandial hyperglycemic states or in type 2 diabetes. However, a molecular mechanism by which glucose activates GLUT2 gene expression is not known. In this study, we report evidence that sterol response element-binding protein (SREBP)-1c plays a key role in glucose-stimulated GLUT2 gene expression. The GLUT2 promoter reporter is activated by SREBP-1c, and the activation is inhibited by a dominant-negative form of SREBP-1c (SREBP-1c DN). Adenoviral expression of SREBP-1c DN suppressed glucose-stimulated GLUT2 mRNA level in primary hepatocytes. An electrophoretic mobility shift assay and mutational analysis of the GLUT2 promoter revealed that SREBP-1c binds to the -84/-76 region of the GLUT2 promoter. Chromatin immunoprecipitation revealed that the binding of SREBP-1c to the -84/-76 region was increased by glucose concentration in a dose-dependent manner. These results indicate that SREBP-1c mediates glucose-stimulated GLUT2 gene expression in hepatocytes.
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http://dx.doi.org/10.2337/diabetes.54.6.1684DOI Listing
June 2005

Identification and characterization of peroxisome proliferator response element in the mouse GLUT2 promoter.

Exp Mol Med 2005 Apr;37(2):101-10

Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea.

In the present study, we show that the expression of type 2 glucose transporter isoform (GLUT2) could be regulated by PPAR-gamma in the liver. Rosiglitazone, PPAR-gamma agonist, activated the GLUT2 mRNA level in the primary cultured hepatocytes and Alexander cells, when these cells were transfected with PPAR-gamma/RXR-alpha. We have localized the peroxisome proliferator response element in the mouse GLUT2 promoter by serial deletion studies and site-directed mutagenesis. Chromatin immunoprecipitation assay using ob/ob mice also showed that PPAR-gamma rather than PPAR-alpha binds to the -197/-184 region of GLUT2 promoter. Taken together, liver GLUT2 may be a direct target of PPAR-gamma ligand contributing to glucose transport into liver in a condition when PAPR-gamma expression is increased as in type 2 diabetes or in severe obesity.
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http://dx.doi.org/10.1038/emm.2005.14DOI Listing
April 2005

SREBP-1c mediates the insulin-dependent hepatic glucokinase expression.

J Biol Chem 2004 Jul 30;279(29):30823-9. Epub 2004 Apr 30.

Department of Biochemistry and Molecular Biology, Yonsei University, Seoul, Korea.

The regulation of hepatic glucose metabolism is important in glucose homeostasis, and liver glucokinase (LGK) plays a central role in this process. Hepatic glucokinase expression is known to be regulated by insulin. Recently it has been suggested that sterol regulatory element binding protein-1c (SREBP-1c) mediates the action of insulin on LGK transcription; however, the precise mechanism is not, to date, well known. In the present study, we identified two functional SREBP-1c response elements, SREa and SREb, in the rat LGK promoter. SREBP-1c could bind to these SREs and activate the LGK promoter, and insulin activated the LGK promoter in Alexander cells. The physical interaction between the protein and SREs of the LGK promoter in vivo was also confirmed. Insulin selectively increased SREBP-1c and LGK expression in primary hepatocytes. Adenoviral expression of SREBP-1c stimulated LGK expression, and the dominant negative mutant of SREBP-1c blocked the increased gene expression of LGK by insulin and SREBP-1c. A chromatin immunoprecipitation assay using primary hepatocytes showed increased binding of SREBP-1 to SREs of the LGK promoter by insulin.
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http://dx.doi.org/10.1074/jbc.M313223200DOI Listing
July 2004

Liver glucokinase can be activated by peroxisome proliferator-activated receptor-gamma.

Diabetes 2004 Feb;53 Suppl 1:S66-70

Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul, Korea.

Thiazolidinediones (TZDs), synthetic ligands of peroxisome proliferator-activated receptor (PPAR)-gamma, are known to decrease hepatic glucose production and increase glycogen synthesis in diabetic animals. Recently it was reported that glucokinase (GK) expression was increased by TZDs in the liver of diabetic ZDF rats. However, the mechanism whereby TZDs increase GK expression is not yet studied. We have assumed that liver type glucokinase (LGK) induction by TZDs could be achieved by direct transcriptional activation. Thus, we have dissected the LGK promoter to explore the presence of a PPAR response element (PPRE) in the promoter. From this study, we were able to localize a PPRE in the -116/-104 region of the rat LGK gene. The PPAR-gamma/retinoid X receptor-alpha heterodimer was bound to the element and activated the LGK promoter. The LGK promoter lacking the PPRE or having mutations in the PPRE could not be activated by PPAR-gamma. Furthermore, troglitazone increased endogenous GK mRNA in primary hepatocytes. These results indicate that PPAR-gamma can directly activate GK expression in liver and may contribute to improving glucose homeostasis in type 2 diabetes.
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http://dx.doi.org/10.2337/diabetes.53.2007.s66DOI Listing
February 2004

Role of peroxisome proliferator-activated receptor-gamma in the glucose-sensing apparatus of liver and beta-cells.

Diabetes 2004 Feb;53 Suppl 1:S60-5

Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul, Korea.

Type 2 diabetes develops in the context of both insulin resistance and beta-cell failure. Thiazolidinediones are a class of antidiabetic agents that are known to improve insulin sensitivity in various animal models of diabetes. The improved insulin sensitivity may be achieved either by systemic insulin sensitization or by direct action of peroxisome proliferator-activated receptor (PPAR)-gamma on the transcription of genes involved in glucose disposal. Evidence supporting the direct action of PPAR-gamma on glucose metabolism is observed in the genes involved in insulin-stimulated glucose disposal. We already showed that GLUT2 and beta-glucokinase were directly activated by PPAR-gamma. Recently, we have identified and characterized the functional PPAR response element in the GLUT2 and liver type glucokinase (LGK) promoter of the liver. It is well known that adipose tissue plays a crucial role in antidiabetic action of PPAR-gamma. In addition, PPAR-gamma can directly affect liver and pancreatic beta-cells to improve glucose homeostasis.
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http://dx.doi.org/10.2337/diabetes.53.2007.s60DOI Listing
February 2004
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