• Biomolecules & Therapeutics
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• v.29 no.5
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• pp.455-464
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• 2021

Uncontrolled inflammation is considered the pathophysiological basis of many prevalent metabolic disorders, such as nonalcoholic fatty liver disease, diabetes, obesity, and neurodegenerative diseases. The inflammatory response is a self-limiting process that produces a superfamily of chemical mediators, called specialized proresolving mediators (SPMs). SPMs include the ω-3-derived family of molecules, such as resolvins, protectins, and maresins, as well as arachidonic acid-derived (ω-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, and alleviation of pain and promote tissue regeneration via novel mechanisms. SPMs function by binding and activating G protein-coupled receptors, such as FPR2/ALX, GPR32, and ERV1, and nuclear orphan receptors, such as RORα. Recently, several studies reported that SPMs have the potential to attenuate lipid metabolism disorders. However, the understanding of pharmacological aspects of SPMs, including tissue-specific biosynthesis, and specific SPM receptors and signaling pathways, is currently limited. Here, we summarize recent advances in the role of SPMs in resolution of inflammatory diseases with metabolic disorders, such as nonalcoholic fatty liver disease and obesity, obtained from preclinical animal studies. In addition, the known SPM receptors and their intracellular signaling are reviewed as targets of resolution of inflammation, and the currently available information on the therapeutic effects of major SPMs for metabolic disorders is summarized.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.40-47
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• 2023

Activation of the NLRP3 inflammasome is a necessary process to induce fibrosis in nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH) is a kind of NAFLD that encompasses the spectrum of liver disease. It is characterized by inflammation and ballooning of hepatocytes during steatosis. We tested whether inhibiting the NLRP3 inflammasome could prevent the development and pathology of NASH. We identified loganin as an inhibitor of the NLRP3 inflammasome and investigated whether in vivo administration of loganin prevented NASH symptoms using a methionine-choline deficient (MCD) diet model in mice. We found that loganin inhibited the NLRP3 inflammasome activation triggered by ATP or nigericin, as shown by suppression of the production of interleukin (IL)-1β and caspase-1 (p10) in mouse primary macrophages. The speck formation of apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) was blocked by loganin, showing that the assembly of the NLRP3 inflammasome complex was impaired by loganin. Administration of loganin reduced the clinical signs of NASH in mice fed the MCD diet, including hepatic inflammation, fat accumulation, and fibrosis. In addition, loganin reduced the expression of NLRP3 inflammasome components in the liver. Our findings indicate that loganin alleviates the inflammatory symptoms associated with NASH, presumably by inhibiting NLRP3 inflammasome activation. In summary, these findings imply that loganin may be a novel nutritional and therapeutic treatment for NASH-related inflammation.

• Journal of Yeungnam Medical Science
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• v.41 no.3
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• pp.150-157
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• 2024

The prevalence of childhood and adolescent obesity has increased and exacerbated during the coronavirus disease 2019 pandemic, both in Korea and globally. Childhood and adolescent obesity poses significant risks for premature morbidity and mortality. The development of serious comorbidities depends not only on the duration of obesity but also on the age of onset. Obesity in children and adolescents affects almost all organ systems, including the endocrine, cardiovascular, gastrointestinal, reproductive, nervous, and immune systems. Obesity in children and adolescents affects growth, cognitive function, and psychosocial interactions during development, in addition to aggravating known adult comorbidities such as type 2 diabetes mellitus, hypertension, dyslipidemia, nonalcoholic fatty liver disease, obstructive sleep apnea, and cancer. Childhood and adolescent obesity are highly associated with increased cardiometabolic risk factors and prevalence of metabolic syndrome. The risk of cardiovascular and metabolic diseases in later life can be considerably decreased by even a small weight loss before the onset of puberty. Childhood and adolescent obesity is a disease that requires treatment and is associated with many comorbidities and disease burdens. Therefore, early detection and therapeutic intervention are crucial.

• Journal of Ginseng Research
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• v.40 no.3
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• pp.203-210
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• 2016

Background: Korean Red Ginseng (KRG) is a well-known natural product with anticarcinogenic and antioxidant effects. We evaluated the antifatigue effect of KRG in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Eighty patients with NAFLD were prospectively randomized to receive 3 wk of KRG or placebo in addition to counseling on healthy eating and regular exercise. Liver function test, proinflammatory cytokines, adiponectin, antioxidant activity, and fatigue score were measured and compared according to the body mass index between the KRG and placebo groups. Results: The liver function tests were significantly improved after 3 wk of treatment in both groups. The mean levels (at baseline and after treatment) of tumor necrosis factor-${\alpha}$ were $108.0pg/mL{\pm}54.8pg/mL$ and $92.7pg/mL{\pm}39.0pg/mL$ (p = 0.018) in the KRG group and $123.1pg/mL{\pm}42.1pg/mL$ and $127.5pg/mL{\pm}62.2pg/mL$ (p = 0.694) in the placebo group, respectively. There was a significant difference in change of adiponectin levels between the KRG ($7,751.2pg/mL{\pm}3,108.1pg/mL$ and $8,197.3pg/mL{\pm}2,714.5pg/mL$) and placebo groups ($7,711.6pg/mL{\pm}3,041.3pg/mL$ and $7,286.1pg/mL{\pm}5,188.7pg/mL$, p = 0.027). In patients with overweight, the fatigue score was significantly decreased in the KRG group ($35.0{\pm}13.2$ and $24.5{\pm}8.9$, p = 0.019). Conclusion: Our results show that KRG might be effective in reducing proinflammatory cytokine and fatigue in overweight patients with NAFLD, in addition to improvements in adiponectin levels.

• Journal of Ginseng Research
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• v.47 no.3
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• pp.429-439
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• 2023

Background: The incidence and clinical importance of nonalcoholic fatty liver disease (NAFLD) has emerged. However, effective therapeutic strategies for NAFLD have yet to be found. Panax ginseng (P. ginseng) is a traditional herb in Eastern Asia with therapeutic effects in many chronic disorders. However, the precise effects of ginseng extract on NAFLD are currently unknown. In present study, the therapeutic effects of Rg3-enriched red ginseng extract (Rg3-RGE) on the progression of NAFLD were explored. Methods: Twelve-week-old C57BL/6 male mice were fed a chow or western diet supplemented with high sugar water solution with or without Rg3-RGE. Histopathology, immunohistochemistry, immunofluorescence, serum biochemistry, western blot analysis, and quantitative RT-PCR were used for in vivo experiment. Conditionally immortalized human glomerular endothelial cell (CiGEnC) and primary liver sinusoidal endothelial cells (LSECs) were used for in vitro experiments. Results: Eight weeks of Rg3-RGE treatment significantly attenuated the inflammatory lesions of NAFLD. Furthermore, Rg3-RGE inhibited the inflammatory infiltrate in liver parenchyma and the expression of adhesive molecules to LSECs. Moreover, the Rg3-RGE exhibited similar patterns on the in vitro assays. Conclusion: The results demonstrate that Rg3-RGE treatment ameliorates NAFLD progression by inhibiting chemotaxis activities in LSECs.

• Journal of Life Science
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• v.33 no.12
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• pp.967-977
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• 2023

Rubus crataegifolius (RC) is a traditional Asian medicinal plant belonging to the Rosaceae family. The fruits of RC are known to prevent adult diseases through antioxidants. In this study, the effects of RC extract (RCex) on obesity and nonalcoholic fatty liver disease (NAFLD) were evaluated in animal models. Twenty-eight male C57BL/6J mice were induced to become obese for 8 weeks and then the extract was orally administered for 8 weeks. RCex reduced body weight, adipose tissue, liver weight. RCex improved biochemical biomarkers including lipid metabolism (alanine aminotransferase (ALT), aspartate aminotransferase (AST), plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol). The activation of AMP-activated protein kinase (AMPK) reduced the expression of adipogenesis genes (liver × receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthesis (FAS), acetyl-CoA carboxylase 1 (ACC1) and the effect of enhancing carnitine palmitoyltransferase (CPT) activity by RCex was verified. RCex also influence on plasma production of hormones (adiponectin & leptin) related on energy expenditure and metabolism. In addition, we confirmed that RCex improved glucose intolerance in HFD-induced obese rats. RCex was first demonstrated to have anti-obesity as well as anti-NAFLD effects by regulating fatty acid oxidation and fatty acid synthesis by phosphorylation of AMPK. This suggests that RCex could be a good supplement for the prevention of obesity and related NAFLD.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.4
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• pp.333-339
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• 2014

Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been known to reverse hepatic steatosis in ob/ob mice. Although many studies have evaluated molecular targets of Ex-4, its mechanism of action on hepatic steatosis and fibrosis has not fully been determined. In the liver, glucose transporter 4 (GLUT4) is mainly expressed in hepatocytes, endothelial cells and hepatic stellate cells (HSCs). In the present study, the effects of Ex-4 on GLUT4 expression were determined in the liver of ob/ob mice. Ob/ob mice were treated with Ex-4 for 10 weeks. Serum metabolic parameters, hepatic triglyceride levels, and liver tissues were evaluated for hepatic steatosis. The weights of the whole body and liver in ob/ob mice were reduced by long-term Ex-4 treatment. Serum metabolic parameters, hepatic steatosis, and hepatic fibrosis in ob/ob mice were reduced by Ex-4. Particularly, Ex-4 improved hepatic steatosis by enhancing GLUT4 via GLP-1R activation in ob/ob mice. Ex-4 treatment also inhibited hepatic fibrosis by decreasing expression of connective tissue growth factor in HSCs of ob/ob mice. Our data suggest that GLP-1 agonists exert a protective effect on hepatic steatosis and fibrosis in obesity and type 2 diabetes.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.9 no.2
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• pp.218-225
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• 2006

Purpose: With a remarkable increase in the prevalence of childhood obesity, the prevalence of nonalcoholic fatty liver disease is assumed to be increasing. The aim of this study is to evaluate the prevalence of nonalcoholic fatty liver disease, hyperlipidemia, and glucose intolerance in normal and obese children. Methods: A total of 2,206 elementary students (boys: 1340, girls: 866) were grouped according to obesity index; normal group and obesity group (mild, moderate, severe). Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) were measured with total cholesterol, triglyceride, and fasting blood glucose. Results: Compared with the 4.6% of elevated aminotransferases in normal group, obese groups showed significantly higher prevalence; 12.1% in mild obesity group, 19.4% in moderate group, and 21.6% in severe group (p<0.0001). The prevalence of hypertriglyceremia was 16.9% in normal weight group, which was significantly lower than obesity group (mild obesity group 30.3%, moderate and severe 37.6%, 38.2% each). In boys, the prevalences of elevated aminotransferases in normal weight and obese groups (mild, moderate, severe) were 6.8%, 18.0%, 23.0%, and 26.0%, respectively (p<0.0001). In girls, those were 2.1%, 5.1%, 12.0%, and 12.6%, respectively (p< 0.0001). The prevalence of hypertriglyceremia was relative to severity of obesity in boys and girls (p<0.0001). Conclusion: The prevalence of elevated serum liver enzymes increased with severity of obesity. For the prevention and treatment of fatty liver and hypertriglycemia, it is important to lower the obesity degree and enforce the education for a weight loss in the student and the parents.

• Journal of Yeungnam Medical Science
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• v.41 no.2
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• pp.103-112
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• 2024

Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic triglyceride content and increased inflammatory macrophage infiltration through the C-C motif chemokine receptor (CCR) 5 pathway in the liver. DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone), is a synthetic derivative of eupatilin that exhibits anti-inflammatory activity in inflammatory bowel disease. However, the effect of DA-6034 on the inflammatory response in NAFLD is not well elucidated. Therefore, we aimed to determine the effect of DA-6034 on hepatic steatosis and inflammation. Methods: Forty male C57BL/6J mice were divided into the following four groups: (1) regular diet (RD), (2) RD with DA-6034, (3) high fat diet (HFD), and (4) HFD with DA-6034. All mice were sacrificed 12 weeks after the start of the experiment. The effects of DA-6034 on macrophages were assessed using RAW 264.7 cells. Results: DA-6034 not only reduced hepatic triglyceride levels and lipid accumulation but also macrophage infiltration and proinflammatory cytokines in HFD-fed mice. According to fluorescence-activated cell sorter analysis, DA-6034 reduced the CD8⁺ T cell fraction in the liver of HFD-fed mice. DA-6034 also reduced CCR5 expression and the migration of liver macrophages in HFD-fed mice and inhibited CCR2 ligand and CCR4 ligand, which stimulated the migration of macrophages. Conclusion: Overall, DA-6034 attenuates hepatic steatosis and inflammation in obesity by regulating CCR5 expression in macrophages.

• Journal of Life Science
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• v.32 no.12
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• pp.962-970
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• 2022

Nonalcoholic steatohepatitis (NASH) is the progressive stage of nonalcoholic fatty liver disease (NAFLD) that highly increases the risk of cirrhosis and liver cancer, and there are few therapeutic options available in the clinic. Poricoic acid (PoA), a component of Poria cocos Wolf, has a wide range of pharmacological activities; however, little is known about its effects on NASH. The preventive effects of PoA on NASH were examined in vivo and in vitro by analyzing triglyceride synthesis, inflammation and fibrosis. In the high fat and methionine-choline deficient diet (HFMCD)-induced NASH mice, PoA reduced the liver weight and the levels of alanine aminotransferase and aspartate aminotransferase compared with non-treated HFMCD group. The staining with Oil Red O and hematoxylin and eosin revealed that PoA administration reduced red staining and the size of lipid droplet. qPCR analysis showed that PoA also reduced the expression of genes related to triglyceride synthesis. Further, immunostaining with CD68 and qPCR analysis revealed that PoA reduced the staining with CD68 and the expression of inflammatory genes induced by HFMCD. Moreover, PoA reduced the staining with sirius red and antibody of α-smooth muscle actin and also reduced the expression of genes related to fibrosis. The treatment of PoA to AML12 cells reduced the increase in triglyceride amount and expression of genes associated with triglyceride synthesis, inflammation and fibrosis. Taken together, our study indicate that PoA has therapeutic effect on NASH through preventing triglyceride synthesis, inflammation and fibrosis.