• Journal of Applied Biological Chemistry
• /
• v.66
• /
• pp.159-164
• /
• 2023

Ferroptosis is a type of regulated cell death recently discovered, characterized by the accumulation of iron-dependent lipid peroxides in the cell membrane, and it involves a complex network of signaling pathways, including iron metabolism, lipid peroxidation, and redox regulation. The dysregulation of these pathways can lead to the induction of ferroptosis and the development of liver diseases, such as alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis, and liver cancer. Studies have demonstrated that targeting key molecules involved in iron metabolism, lipid peroxidation, and redox regulation can reduce liver injury and improve liver function in different liver diseases by inhibiting ferroptosis. Thus, modulation of ferroptosis presents a promising therapeutic target for treating liver diseases. However, further research is required to gain a more comprehensive understanding of the mechanisms underlying the role of ferroptosis in liver diseases and to develop more effective and targeted treatments.

• Pediatric Gastroenterology, Hepatology & Nutrition
• /
• v.15 no.1
• /
• pp.44-51
• /
• 2012

Purpose: Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) polymorphism has been suggested to play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in obese adults, and known to be a mediator of insulin resistance. In this study, we evaluated the role of TNF-${\alpha}$ promoter polymorphisms and insulin resistance in the development of NAFLD in obese children. Methods: A total of 111 obese children (M:F=74:37; mean age, $11.1{\pm}2.0$ yrs) were included. The children were divided into 3 groups: controls (group I, n=61), children with simple steatosis (group II, n=17), and children with non-alcoholic steatohepatitis (group III, n=33). Serum TNF-${\alpha}$ levels, homeostasis model assessment of insulin resistance (HOMA-IR), and TNF-${\alpha}$ -308 and -238 polymorphisms were evaluated. Results: There were no differences in TNF-${\alpha}$ polymorphism at the -308 or the -238 loci between group I and group II + III ($p$=0.134 and $p$=0.133). The medians of HOMA-IR were significantly different between group I and group II + III ($p$=0.001), with significant difference between group II and group III ($p$=0.007). No difference was observed in the HOMA-IR among the genotypes at the -308 locus ($p$=0.061) or the -238 locus ($p$=0.207) in obese children. Conclusion: TNF-${\alpha}$ promoter polymorphisms at the -308 and -238 loci were not significantly associated with the development of NAFLD in children; nevertheless, insulin resistance remains a likely essential factor in the pathogenesis of NAFLD in obese children, especially in the progression to NASH.

• The Journal of Pediatrics of Korean Medicine
• /
• v.32 no.4
• /
• pp.1-12
• /
• 2018

Objectives Bangpungtongsungsan is an herbal medicine that treats obesity and dampness-phlegm. The aim of this study was to investigate the efficacy of Bangpungtongsungsan on insulin resistance induced by non-alcoholic fatty liver disease. Methods Male 6-week-old C57BL/6 male mice were divided into four groups: control group (Ctrl), high fat diet group (HFF), high fat diet with Bangpungtongsungsan extract administration group (BT1), and high fat diet with double concentration of Bangpungtongsungsan extract administration group (BT2). Each 10 mice were allocated to each group (total of 40 mice). All mice were allowed to eat fat rich diet freely throughout the experiment. To examine the effect of Bangpungtongsungsan, we observed weight changes, lipid blot distributions, PGC-1, $p-I{\kappa}B$, 8-OHdG, p-JNK, total cholesterol and glucose levels. Results Comparing of body weight measurements between 4 groups, weight gain was significantly lower in BT1 and BT2 group than the HFF group. The distribution of lipid blots and positive reaction of PGC-1 were significantly lower in BT1 and BT2 group. The positive reaction of $p-I{\kappa}B$ and 8-OHdG in hepatic tissues was significantly lower in BT1 and BT2 group. The positive reaction of p-JNK in hepatic tissues was significantly lower in BT1 and BT2 group. Total cholesterol and glucose levels were significantly lower in BT1 and BT2 group. Conclusions Bangpungtongsungsan has the effect of improving non-alcoholic fatty liver induced insulin resistance through regulation of lipid metabolism.

• BMB Reports
• /
• v.45 no.7
• /
• pp.396-401
• /
• 2012

Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by an accumulation of lipids (triglycerides) in hepatocytes and is often accompanied by high plasma levels of free fatty acids (FFA). In this study, we compared the energy metabolism in acute steatotic and non-steatotic primary mouse hepatocytes. Acute steatosis was induced by pre-incubation with high concentrations of oleate and palmitate. Labeling experiments were conducted using [$U-^{13}C_5$,$U-^{15}N_2$] glutamine. Metabolite concentrations and mass isotopomer distributions of intracellular metabolites were measured and applied for metabolic flux estimation using transient $^{13}C$ metabolic flux analysis. FFAs were efficiently taken up and almost completely incorporated into triglycerides (TAGs). In spite of high FFA uptake rates and the high synthesis rate of TAGs, central energy metabolism was not significantly changed in acute steatotic cells. Fatty acid ${\beta}$-oxidation does not significantly contribute to the detoxification of FFAs under the applied conditions.

• Experimental and Molecular Medicine
• /
• v.50 no.12
• /
• pp.2.1-2.12
• /
• 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.

• BMB Reports
• /
• v.53 no.6
• /
• pp.317-322
• /
• 2020

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. NAFLD can further progress to irreversible liver failure such as non-alcoholic steatohepatitis (NASH) fibrosis and cirrhosis. However, specific regulator of NASH-fibrosis has yet to be established. Here, we found that glutathione peroxidase 7 (GPx7) was markedly expressed in NASH fibrosis. Although GPx7 is an antioxidant enzyme protecting other organs, whether GPx7 plays a role in NASH fibrosis has yet to be studied. We found that knockdown of GPx7 in transforming growth factor-β (TGF-β) and free fatty acids (FFA)-treated LX-2 cells elevated the expression of pro-fibrotic and pro-inflammatory genes and collagen synthesis. Consistently, GPx7 overexpression in LX-2 cells led to the suppression of ROS production and reduced the expression of pro-fibrotic and pro-inflammatory genes. Further, NASH fibrosis induced by choline-deficient amino acid defined, high fat diet (CDAHFD) feeding was significantly accelerated by knockdown of GPx7, as evidenced by up-regulated liver fibrosis and inflammation compared with CDAHFD control mice. Collectively, these results suggest that GPx7 might be a novel therapeutic target to prevent the progression and development of NAFLD.

• Journal of Korean Medicine for Obesity Research
• /
• v.15 no.1
• /
• pp.1-8
• /
• 2015

Objectives: The aim of this study was to evaluate the effectiveness and safety of electroacupuncture for non-alcoholic fatty liver disease (NAFLD). Methods: A randomized, controlled pilot trial was conducted. Twenty-two participants were randomized into one of the two groups: an acupuncture group (n=11) and wait-list group (n=11). The treatment group received 8 sessions of electroacupuncture over 8 weeks. Twenty points (CV4, CV12, both LR14, GB26, ST25, ST34, ST40, ST36, SP4, SP6, LR3) were selected for needling. The control group did not receive acupuncture treatment during study period and followup were done in the 4th and 8th weeks after randomization in both groups. The primary outcome was body fat computed tomography and the secondary outcomes included blood test (aspartate aminotransferase, alanine transferase, triglyceride, total cholesterol, high density lipoproteincholesterol, low density lipoprotein-cholesterol, blood sugar test, ${\gamma}$-guanosine triphosphate) and body composition test (body mass index, weight, body fat mass, body fat rate, waist hip ratio). Safety was assessed at every visit. Results: There was no significant differences in between the experimental group and control group. There were no adverse events. Conclusions: The results suggest that In patients with NAFLD, electroacupuncture treatment did not induce worsening of liver disease and liver function, but it was no improvement symptoms of fatty liver. Study of herb medicine treatments and other acupuncture therapy of NAFLD are required later.

• Korean Journal of Medicinal Crop Science
• /
• v.28 no.4
• /
• pp.276-286
• /
• 2020

Background: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with multiple metabolic disorders. The medicinal plant Curcuma longa L. is widely distributed in Asia and has been used to treat a spectrum diseases in clinical practice. To date, there are inadequate reports of the effects of C. longa 50% EtOH extract (CE) on NAFLD. Therefore, in this study, we evaluate the CE on an NAFLD animal and elucidate the mechanism of action. Methods and Results: C57BL/6J mice fed a methionine-choline deficient diet (MCD) were treated with CE or milk thistle, and changes in inflammation and stetosis were assessed. Experimental animals were divided into six group (n = 10); Normal, MCD, MCD + CE 50 mg/kg/day (CE 50), MCD + CE 100 mg/kg/day (CE 100), MCD + CE 150 mg/kg/day (CE 150), and the Control, MCD + Milk thistle 150 mg/kg/day (MT 150). Body weight, liver weight, liver function, and histological changes were assessed in experimental animals. Quantitative real-time polymerase chain reaction and western blot analyses were performed on samples collected after 4 weeks of treatment. We observed that CE administration improved MCD-diet-induced lipid accumulation, and triglyceride (TG) and total cholesterol (TC) levels in serum. Treatment with CE also decreased hepatic lipogenesis through modulation of the sterol regulatory element binding protein-1 (SREBP-1), CCAAT-enhancer binding protein α (C/EBPα), fatty acid synthase (FAS), and peroxisome proliferator-activated receptor γ (PPARγ) expresion. In addition, the use of CE increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and inhibited the up-regulation of toll-like receptor (TLR)-2 and TLR-4 signaling and the production of inflammatory mediators. Conclusions: In this report, we observed that CE regulated lipid accumulation in an MCD dietinduced NAFLD model by decreasing lipogenesis. These data suggeste that CE could effectively protect mice against MCD-induced NAFLD, by inhibiting the TLR-2 and TLR-4 signaling cascades.

• The Korea Journal of Herbology
• /
• v.33 no.6
• /
• pp.61-70
• /
• 2018

Objectives : Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of hepatic triglycerides (TG) that leads to inflammation and fibrosis. Crataegi Fructus ethanol extract (CE) is a korean traditional herb that used for digestive diseases. It has been investigated that CE has the effect that prevent hepatotoxicity caused by CCl4 or GaIN and regulate the inflammatory in several organs. However, a hypolipidemic effect of CF has not been reported. Methods : The purpose of this study is that examine the lipid accumulation inhibitory effect of CE on NAFLD. We checked the body and liver weight change of MCD-diet induced mice with/without administration of CE. The blood lipid levels of C57BL/6J mice were checked by biochemistry. Also we observed the liver histology of MCD-diet induced mice and investigate the molecular mechanisms in MCD-diet-induced NAFLD in C57BL/6J mice. Results : CE improved MCD-diet-induced lipid accumulation and TG and TC levels. Also, CE decreased hepatic lipogenesis such as SREBP-1, $C/EBP{\alpha}$, $PPAR{\gamma}$, ACC and FAS. Besides, we also found out that CE increased AMPK phosphorylation. These results indicated that CE has the same ability to activate AMPK and then reduce SREBP-1, and FAS expression, finally leading to inhibit hepatic lipogenesis and hepatic antioxidative ability. Conclusions : In this report, we found CE exerted a regulatory effect on lipid accumulation by decreasing lipogenesis in MCD-diet induced NAFLD model. Therefore, CE extract may be active in the prevention of fatty liver.

• Pediatric Gastroenterology, Hepatology & Nutrition
• /
• v.15 no.2
• /
• pp.74-78
• /
• 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.