• 대한한방내과학회지
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• 제39권3호
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• pp.302-312
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• 2018

Objectives: This study was performed to investigate the effects of two herbal medicines, Agastachis Herba and Lysimachiae Herba, on a cellular model of non-alcoholic fatty liver diseases (NFLDs). Methods: HepG2 cells were treated with palmitic acid and with various concentrations of Agastachis Herba (AH) or Lysimachiae Herba (LH) extract in water. The lipotoxicity was assessed using EZ-cytox, and the lipoapoptosis was assessed using cell death detection ELISA. Intracellular lipids were measured by oil red O staining. The efficacy of AH and LH on sterol regulatory element-binding transcription factor-1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) in HepG2 cells was measured by reverse transcription polymerase chain reaction (RT-PCR). Results: Both AH and LH extracts increased lipoapoptosis and decreased lipotoxicity and levels of SREBP-1c, ACC, and FAS (SREBP-1c, ACC, and FAS are factors in lipid synthesis). In the oil red O staining experiment, both extracts also reduced intracellular lipid accumulation; in this instance, LH's efficacy was superior to that of AH. Conclusions: According to the results, both AH and LH are likely to contribute to non-alcoholic fatty liver disease, as both interfere with lipid synthesis.

• Nutrition Research and Practice
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• 제15권3호
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• pp.294-308
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• 2021

BACKGROUD/OBJECTIVES: Allomyrina dichotoma larva (ADL), one of the many edible insects recognized as future food resources, has a range of pharmacological activities. In a previous study, an ADL extract (ADLE) reduced the hepatic insulin resistance of high-fat diet (HFD)-induced diabetic mice. On the other hand, the associated molecular mechanisms underlying pancreatic beta-cell dysfunction remain unclear. This study examined the effects of ADLE on palmitate-induced lipotoxicity in a beta cell line of a rat origin, INS-1 cells. MATERIALS/METHODS: ADLE was administered to high-fat diet treated mice. The expression of apoptosis-related molecules was measured by Western blotting, and reactive oxidative stress generation and nitric oxide production were measured by DCH-DA fluorescence and a Griess assay, respectively. RESULTS: The administration of ADLE to HFD-induced diabetic mice reduced the hyperplasia, 4-hydroxynonenal levels, and the number of apoptotic cells while improving the insulin levels compared to the HFD group. Treatment of INS-1 cells with palmitate reduced insulin secretion, which was attenuated by the ADLE treatment. Furthermore, the ADLE treatment prevented palmitate-induced cell death in INS-1 cells and isolated islets by reducing the apoptotic signaling molecules, including cleaved caspase-3 and PARP, and the Bax/Bcl2 ratio. ADLE also reduced the levels of reactive oxygen species generation, lipid accumulation, and nitrite production in palmitate-treated INS-1 cells while increasing the ATP levels. This effect corresponded to the decreased expression of inducible nitric oxide synthase (iNOS) mRNA and protein. CONCLUSIONS: ADLE helps prevent lipotoxic beta-cell death in INS-1 cells and HFD-diabetic mice, suggesting that ADLE can be used to prevent or treat beta-cell damage in glucose intolerance during the development of diabetes.

• 대한한방내과학회지
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• 제33권4호
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• pp.429-437
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• 2012

Objectives : Obesity is an important cause of diabetes, and lipotoxicity causes insulin resistance. In this study, we investigated the effects of Salvia miltiorrhiza on high fat diet-induced obese type 2 diabetic mouse models. Methods : Diabetes was induced in ICR male mouse (23~25 g) with Surwit's high fat, high sucrose diet. Mice were divided into 4 groups (n=10) of normal, control, Salvia miltiorrhiza, and metformin. After 8 weeks, body weight, OGTT, fructosamine, lipid profile, serum level of adiponectin and leptin, epididymal fat pad, liver weight and epididymal adipocyte size were measured. Results : Salvia miltiorrhiza significantly reduced oral glucose tolerance levels, fructosamine serum level, epididymal fat weight, and epididymal adipocyte size. Salvia miltiorrhiza also increased HDL-cholesterol, adiponectin and leptin serum levels. Conclusions : These results show that Salvia miltiorrhiza improves insulin resistance. Therefore we suggest that Salvia miltiorrhiza would be an effective treatment for obese type 2 diabetic patients.

• International Journal of Oral Biology
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• 제43권1호
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• pp.23-27
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• 2018

Increased intracellular levels of $Ca^{2+}$ are generally thought to negatively regulate lipolysis in mature adipocytes, whereas store-operated $Ca^{2+}$ entry was recently reported to facilitate lipolysis and attenuate lipotoxicity by inducing lipophagy. Transient receptor potential mucolipin1 (TRPML1), a $Ca^{2+}$-permeable non-selective cation channel, is mainly expressed on the lysosomal membrane and plays key roles in lysosomal homeostasis and membrane trafficking. However, the roles of TRPML1 in lipolysis remains unclear. In this study, we examined whether the channel function of TRPML1 induces lipolysis in mature adipocytes. We found that treatment of mature adipocytes with ML-SA1, a specific agonist of TRPML1, solely upregulated extracellular glycerol release, but not to the same extent as isoproterenol. In addition, knockdown of TRPML1 in mature adipocytes significantly reduced autophagic flux, regardless of ML-SA1 treatment. Our findings demonstrate that the channel function of TRPML1 partially contributes to lipid metabolism and autophagic membrane trafficking, suggesting that TRPML1, particularly the channel function of TRPML1, is as therapeutic target molecule for treating obesity.

• Journal of Yeungnam Medical Science
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• 제36권2호
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• pp.67-77
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• 2019

The paradigm of chronic liver diseases has been shifting. Although hepatitis B and C viral infections are still the main causes of liver cirrhosis and hepatocellular carcinoma (HCC), the introduction of effective antiviral drugs may control or cure them in the near future. In contrast, the burden of nonalcoholic fatty liver disease (NAFLD) has been increasing for decades, and 25 to 30% of the general population in Korea is estimated to have NAFLD. Over 10% of NAFLD patients may have nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. NASH can progress to cirrhosis and HCC. NASH is currently the second leading cause to be placed on the liver transplantation list in the United States. NAFLD is associated with obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. The pathophysiology is complex and associated with lipotoxicity, inflammatory cytokines, apoptosis, and insulin resistance. The only proven effective treatment is weight reduction by diet and exercise. However, this may not be effective for advanced fibrosis or cirrhosis. Therefore, effective drugs are urgently needed for treating these conditions. Unfortunately, no drugs have been approved for the treatment of NASH. Many pharmaceutical companies are trying to develop new drugs for the treatment of NASH. Some of them are in phase 2 or 3 clinical trials. Here, pharmacologic therapies in clinical trials, as well as the basic principles of drug therapy, will be reviewed, focusing on pathophysiology.

• 비만대사연구학술지
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• 제1권2호
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• pp.66-73
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• 2022

Obesity is an increasing public health and medical issue worldwide. It has been associated with several comorbidities, including diabetes, cardiovascular disease, stroke, and cancer. Chronic kidney disease (CKD) is another important comorbidity of obesity. Other major causes of CKD include hypertension and diabetes. However, the association between obesity and CKD is often overlooked. Among patients with CKD, patients with obesity were more vulnerable to have rapid kidney function decline than that of those with normal weight. Additionally, CKD is more prevalent among patients with obesity. These aggravations are induced through multiple mechanisms, specifically metabolic impairment of obesity and mechanical burden because of increasing intraabdominal renal pressure. Furthermore, the inflammation and lipotoxicity, caused by obesity, are critical in the CKD aggravation in patients with obesity. To prevent this, all adult patients with obesity are tested for CKD. The workup includes the estimated glomerular filtration rate and regular follow-up. Step-wise management is required for patients with obesity with CKD. Prompt reduction and management of obesity effectively delay CKD progression among patients with obesity and CKD. Therefore, weight loss is a core management for patients with obesity and CKD. Based on several studies, this article focused on the association between CKD and obesity, as well as the diagnosis and weight management of patients with obesity and CKD.

• IMMUNE NETWORK
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• 제22권2호
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• pp.19.1-19.20
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• 2022

Coxsackievirus B3 (CVB3) infection causes acute pancreatitis and myocarditis. However, its pathophysiological mechanism is unclear. Here, we investigated how lipid metabolism is associated with exacerbation of CVB3 pathology using high-fat diet (HFD)-induced obese mice. Mice were intraperitoneally inoculated with 1×10⁶ pfu/mouse of CVB3 after being fed a control or HFD to induce obesity. Mice were treated with mitoquinone (MitoQ) to reduce the level of mitochondrial ROS (mtROS). In obese mice, lipotoxicity of white adipose tissue-induced inflammation caused increased replication of CVB3 and mortality. The coxsackievirus adenovirus receptor increased under obese conditions, facilitating CVB3 replication in vitro. However, lipid-treated cells with receptor-specific inhibitors did not reduce CVB3 replication. In addition, lipid treatment increased mitochondria-derived vesicle formation and the number of multivesicular bodies. Alternatively, we found that inhibition of lipid-induced mtROS decreased viral replication. Notably, HFD-fed mice were more susceptible to CVB3-induced mortality in association with increased levels of CVB3 replication in adipose tissue, which was ameliorated by administration of the mtROS inhibitor, MitoQ. These results suggest that mtROS inhibitors can be used as potential treatments for CVB3 infection.

• 생명과학회지
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• 제28권10호
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• pp.1233-1243
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• 2018

SREBPs는 지질의 항상성 및 대사를 조절하는 전사 인자이다. 이들은 내인성 콜레스테롤, 지방산(FA), 트리아실글리세롤(TG) 및 인지질 합성에 필요한 효소의 발현을 정밀하게 조절한다. 3종류의 SREBP 단백질은 2개의 다른 유전자에 의해 암호화 된다. SREBP1 유전자는 SREBP-1a와 SREBP-1c를 만든다. 이는 RNA의 alternative splicing에 의한 대체 프로모터의 이용으로부터 유도된다. SREBP-2는 별도의 유전자에서 유래한다. 또한, SREBPs는 ER 스트레스, 염증, 자가포식 및 세포사멸과 같은 수많은 병인과정에 관여하며, 비만, 이상 지질혈증, 당뇨병 및 비알콜성 지방간 질환 등을 유발하는 것으로 알려져 있다. 유전체의 분석은 SREBPs가 생물학적 신호 전달, 세포 신진 대사, 및 성장을 조절하는 중요한 연결고리임을 보여 주었다. 이 과정에서 SREBP는 PI3K-Akt-mTOR 경로를 통해 활성화 된다고 알려져 있다. 하지만 정확한 분자 메커니즘은 좀더 밝혀져야 한다. 이 리뷰에서는 세포, 기관 및 생물개체 수준의 생리학 및 병태 생리학 영역에서 SREBP의 역할에 대한 포괄적인 이해를 넓혀 줄 것이다.