• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제15권2호
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• pp.74-78
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• 2012

With a markedly increased prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) now becomes the most common cause of chronic liver disease in both adults and children. The etiology and pathogenesis of NAFLD are multifactorial and remain incompletely understood. According to the "two-hit" theory, inflammatory cytokines and adipokines are activated by oxidative stress and they are involved in insulin resistance, necroinflammatory steatohepatitis and fibrosis. This review discusses the latest updates on the role of some of important inflammatory adipokines and cytokines in the pathogenesis of NAFLD with an emphasis on their potential therapeutic implications.

• BMB Reports
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• 제42권8호
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• pp.475-481
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• 2009

Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.

• BMB Reports
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• 제55권10호
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• pp.481-487
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• 2022

Over the past few years, hydrogen sulfide (H₂S) has been shown to exert several biological functions in mammalian. The endogenous production of H₂S is mainly mediated by cystathione β-synthase, cystathione γ-lyase and 3-mercaptopyruvate sulfur transferase. These enzymes are broadly expressed in liver tissue and regulates liver function by working on a variety of molecular targets. As an important regulator of liver function, H₂S is critically involved in the pathogenesis of various liver diseases, such as non-alcoholic steatohepatitis and liver cancer. Targeting H₂S-generating enzymes may be a therapeutic strategy for controlling liver diseases. This review described the function of H₂S in liver disease and summarized recent characterized role of H₂S in several cellular process of the liver.

• Experimental and Molecular Medicine
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• 제50권12호
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• pp.2.1-2.12
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• 2018

Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH.

• 보건행정학회지
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• 제31권4호
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• pp.472-478
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• 2021

Background: Early identification of patients who are highly likely to develop severe illness among confirmed cases of coronavirus disease 19 (COVID-19) can be expected to lead to effective treatment. This study therefore aimed to determine whether the presence of nonalcoholic fatty liver disease (NAFLD) has an impact on the exacerbation of COVID-19 symptoms. Methods: The study used the Korean National Health Insurance claim data for treatment of COVID-19 patients in 2020. NAFLD includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The outcome variables used were hospitalization and the use of medical devices. Hospitalization was defined by a length of stay exceeding one day and the use of medical devices was defined as one or more uses of a ventilator or extracorporeal membrane oxygenation. Multivariable logistic regression analysis was performed to determine if there was a difference in the hospitalization and use of medical devices of COVID-19 patients depending on the presence of NAFLD. Results: The odds ratio of hospitalization was 1.059, indicating slightly higher odds of hospitalization for patients with NAFL or NASH compared to those without the conditions, but it was not statistically significant (0.969-1.156). On the other hand, the odds ratio of use of medical devices was high at 1.667 and was statistically significant (1.111-2.501). Conclusion: The study results found NAFLD to be a risk factor that can exacerbate symptoms in COVID-19 patients. Accordingly, it is necessary to identify NAFLD patients through preemptive screening and provide them with appropriate treatments.

• 대한한방내과학회지
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• 제43권4호
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• pp.606-624
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• 2022

Objective: The aim of this study was to compare the effects of different doses of Geumnyeonyijin-tang (GNYJT) water extracts with those of metformin (250 mg/kg) in mild diabetic-obese mice. Methods and Results: The 48 mice were divided into 1 normal pellet diet (NFD) group and 5 high-fat diet (HFD) groups. At the end of 12 weeks of oral administration of metformin (250 mg/kg) or GNYJT water extracts (400, 200, or100 mg/kg), the effects were evaluated. The HFD control mice showed noticeable increases in body weight, adipose tissue density, fat pad weight of the periovarian and abdominal wall, and insulin, blood glucose, and HbA1c levels, with decreases in serum HDL levels. Increases in the periovarian and dorsal abdominal fat pad, regions of steatohepatitis, adipocyte hypertrophy, and hepatocyte hypertrophy were also discovered. The HFD group showed a decline in glucose levels and elevation of hepatic gluconeogenesis, suggesting an HFD-induced AMPK downregulation related to glucose dysregulation, as well as lipid metabolism related to obese insulin-resistant type II diabetes, dyslipidemia, and oxidative stress related diabetic hepatopathy (non-alcoholic fatty liver disease, NAFLD). Conclusion: Assessment of the key parameters for inhibition of diabetes and related complications in HFD-fed diabetic-obese mice demonstrated that GNYJT water extracts have favorable ameliorating effects. The effect of GNYJT was manifested through the stimulation of AMPK upregulation of related hepatic glucose enzyme activities and expression of lipid metabolism-related genes. Therefore, appropriate oral dosages of GNYJT could be promising as a new preventive candidate for controlling diabetes and related complications. Further screening of biologically active compounds, elucidation of detailed mechanisms, and more animal studies are warranted.

• Molecules and Cells
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• 제46권8호
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• pp.496-512
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• 2023

A fructose-enriched diet is thought to contribute to hepatic injury in developing non-alcoholic steatohepatitis (NASH). However, the cellular mechanism of fructose-induced hepatic damage remains poorly understood. This study aimed to determine whether fructose induces cell death in primary hepatocytes, and if so, to establish the underlying cellular mechanisms. Our results revealed that treatment with high fructose concentrations for 48 h induced mitochondria-mediated apoptotic death in mouse primary hepatocytes (MPHs). Endoplasmic reticulum stress responses were involved in fructose-induced death as the levels of phosho-eIF2α, phospho-C-Jun-N-terminal kinase (JNK), and C/EBP homologous protein (CHOP) increased, and a chemical chaperone tauroursodeoxycholic acid (TUDCA) prevented cell death. The impaired oxidation metabolism of fatty acids was also possibly involved in the fructose-induced toxicity as treatment with an AMP-activated kinase (AMPK) activator and a PPAR-α agonist significantly protected against fructose-induced death, while carnitine palmitoyl transferase I inhibitor exacerbated the toxicity. However, uric acid-mediated toxicity was not involved in fructose-induced death as uric acid was not toxic to MPHs, and the inhibition of xanthine oxidase (a key enzyme in uric acid synthesis) did not affect cell death. On the other hand, treatment with inhibitors of the nicotinamide adenine dinucleotide (NAD)⁺-consuming enzyme CD38 or CD38 gene knockdown significantly protected against fructose-induced toxicity in MPHs, and fructose treatment increased CD38 levels. These data suggest that CD38 upregulation plays a role in hepatic injury in the fructose-enriched diet-mediated NASH. Thus, CD38 inhibition may be a promising therapeutic strategy to prevent fructose-enriched diet-mediated NASH.

• 대한임상검사과학회지
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• 제47권4호
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• pp.251-258
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• 2015

커큐민(curcumin)은 강황 내 주요 폴리페놀 화합물의 한 성분으로 비만과 관련된 비알코올성 지방간염을 막아 주는 것으로 잘 알려져 있다. 이 연구의 목적은 고지방 식이로 키운 비만 마우스에서 사염화탄소($CCl_4$)로 유발한 간섬유증에 미치는 커큐민의 보호효과를 조사하기 위해 시도하였다. 군간 비교를 위해, 정상 식이와 고지방 식이로 키운 마우스에 7주간 $CCl_4$를 투여하면서 동시에 커큐민을 투여한 것과 투여하지 않은 군으로 나누었으며, 체중이나 혈당과 같은 대사 프로파일이나 지방세포의 크기 및 간섬유증의 변화를 조사하기 위해 혈청 생화학적 검사, 조직학적 검사 및 면역조직화학적 검사를 수행하였다. 또한 간세포 내자멸세포의 관찰을 위해 TUNEL 법을 사용하였다. 그 결과 고지방식이+$CCl_4$ 마우스에 커큐민을 투여한 군에서는 투여하지 않은 군에 비해 체중, 공복혈당 수치, 혈청 AST, ALT 수치가 낮았고, 지방조직 내의 지방세포 크기와 대식세포 및 비만세포 수가 감소하였다. 이와 반대로 정상식이+$CCl_4$ 마우스에 커큐민을 투여한 경우에는 투여하지 않은 군에 비해 체중과 비만세포 수 이외에는 통계학적인 차이가 없었다. 더욱이 커큐민은 간조직의 간실질세포의 자멸세포 수는 줄인 반면 활성 간성상세포 모양의 비실질세포의 자멸세포 수를 증가시켰다. 이 결과를 종합해 볼 때 커큐민은 비만 마우스의 간질환 진행에서 효과적인 항섬유 치료제로서 사용할 수 있을 것으로 사료된다.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제13권1호
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• pp.51-57
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• 2010

목 적: 뇌하수체저하증 환아들은 비만, 당불내성, 고지질혈증을 포함한 대사증후군의 양상을 보인다. 이 연구의 목적은 뇌하수체저하증과 연관된 소아 지방간질환의 임상 양상과 간조직 소견을 알아보는 것이다. 방 법: 뇌하수체저하증 환자 중에서 비알코올성 지방간질환으로 진단된 소아 11명의 임상자료를 조사하였다. 결 과: 뇌하수체저하증 진단 시 연령은 10.4${\pm}$3.2세였다. 지방간질환 진단 시 연령은 13.1${\pm}$2.7세였다. 두 개인 두종이 뇌하수체저하증의 기저질환 중 가장 흔하였다. 지방간질환 진단 당시 체질량지수 85백분위수 이상이 9명(82%), 금식 시 고혈당이 5명(45%), 고지질혈증이 9명(82%)에서 발견되었다. 신장의 표준편차 점수의 평균은 뇌하수체저하증 진단 시보다 지방간질환 진단시에 유의하게 낮았다. 간생검을 실시한 6명 중에서 1명은 간경변, 2명은 연결 섬유화가 동반된 지방간염, 2명은 경도의 간문맥 섬유화가 동반된 지방간염, 1명은 단순 지방간으로 진단되었다. 결 론: 뇌하수체저하증을 가진 소아는 저신장, 비만, 고지질혈증, 비알코올성 지방간질환이 발생할 위험이 높다. 간조직의 진행된 섬유화가 흔하기 때문에 뇌하수 체저하증 환아에서 지방간질환의 조기 진단이 중요하다.