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Review : Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis
( Seung Hoi Koo ) 대한간학회 2013 Clinical and Molecular Hepatology(대한간학회지) Vol.19 No.3
Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD. ((Iin Mol Hepatol 2013;19:210-215)
Bae, Ui-Jin,Park, John,Park, Il Woon,Chae, Byung Min,Oh, Mi-Ra,Jung, Su-Jin,Ryu, Geon-Seek,Chae, Soo-Wan,Park, Byung-Hyun World Scientific Publishing Company 2018 The American journal of Chinese medicine Vol.46 No.3
<P>The prevalence of metabolic diseases has risen globally in parallel with the obesity epidemic over the past few decades. Green tea has been reported to have metabolically beneficial effects on obesity; however, the mechanism by which green tea regulates lipid metabolism is not clearly understood. Male c57BL/6 mice were fed a normal chow diet, a high-fat diet (HFD), or an HFD supplemented with various doses of epigallocatechin gallate-rich green tea extract (GTE) for 12 weeks. GTE supplementation reduced body weight gain, prevented hepatic fat accumulation, decreased hypertriglyceridemia, and improved hyperglycemia and insulin resistance in HFD-fed mice. The underlying mechanisms of these beneficial effects of GTE might involve the upregulation of sirtuin 1 and AMP activated protein kinase (AMPK) and the downregulation of enzymes related to <I>de novo</I> lipogenesis. Consistent with the <I>in vivo</I> findings, GTE increased the expression and activity of sirtuin 1, enhanced the binding of sirtuin 1 to liver kinase B1 (LKB1) and subsequent deacetylation of LKB1, and reduced triglyceride accumulation in HepG2 cells. These results suggest the possible therapeutic potential of dietary epigallocatechin gallate-rich GTE supplementation for preventing the development and progression of hepatic steatosis and obesity.</P>
김예진,김현경,강수민,김하윤,고광웅 한국식품과학회 2023 Food Science and Biotechnology Vol.32 No.10
Rottlerin is isolated from Mallotus japonicus, a plant rich in polyphenols. Rottlerin is a selective PKCδ-inhibitor and is also known as an uncoupler of oxidative phosphorylation and anti-neoplastic agent. However, its anti-obesity effect is yet to be established. Therefore, this study tested whether rottlerin inhibits adipogenesis and de novo lipogenesis via the LRP6/mTOR/SREBP1C pathway in 3T3-L1 adipocytes. Rottlerin dramatically decreased lipid accumulation assessed by Oil Red O as evidence to support the cellular phenotype (p < 0.001). Pivotal messenger RNA and protein expressions associated with de novo lipogenesis (SREBP1C, ACC1, FAS, and SCD1) and adipogenesis (PPARγ and C/EBPα) were subsequentially verified by rottlerin in a dose-dependent manner (p < 0.05). Further investigation revealed that rottlerin reduced the AKT/mTOR pathway via diminished total protein of LRP6 (p < 0.05). Collectively, these findings establish a causal link between rottlerin, LRP6, and the altered nutrient-sensing mTOR pathway, in which rottlerin regulates de novo lipogenesis and adipogenesis in white adipocytes.
( Hyemyoung Ahn ),( Jeongho Jeong ),( Knowledge Mudhibadi Moyo ),( Yungsun Ryu ),( Bokkee Min ),( Seong Ho Yun ),( Hwa Yeon Kim ),( Wooki Kim ),( Gwang-woong Go ) 한국미생물생명공학회(구 한국산업미생물학회) 2017 Journal of microbiology and biotechnology Vol.27 No.11
Korean red pine (Pinus densiflora) bark extract, PineXol (PX), was investigated for its potential antioxidant and anti-inflammation effects in vitro. It was hypothesized that PX treatment (25- 150 μg/ml) would reduce the lipid synthesis in HepG2 hepatocytes as well as lipid accumulation in 3T3-L1 adipocytes. Hepatocytes’ intracellular triglycerides and cholesterol were decreased in the PX 150 μg/ml treatment group compared with the control (p < 0.05). Consequently, de novo lipogenic proteins (acetyl-CoA carboxylase 1, stearoyl-CoA desaturase 1, elongase of very long chain fatty acids 6, glycerol-3-phosphate acyltransferase 1, and sterol regulatory element-binding protein 1) were significantly decreased in hepatocytes by PX 150 μg/ml treatment compared with the control (p < 0.05). In differentiated 3T3-L1 adipocytes, the lipid accumulation was significantly attenuated by all PX treatments (p < 0.01). Regulators of adipogenesis, including CCAAT-enhancer-binding proteins alpha, peroxisome proliferator-activated receptor gamma, and perilipin, were decreased in PX 100 μg/ml treatment compared with the control (p < 0.05). In conclusion, PX might have anti-obesity effects by blocking hepatic lipogenesis and by inhibiting adipogenesis in adipocytes.
( Gwang Woong Go ),( Sangnam Oh ),( Miri Park ),( Gyoungok Gang ),( Danielle Mclean ),( Han Sul Yang ),( Min Ho Song ),( Young Hoon Kim ) 한국미생물 · 생명공학회 2013 Journal of microbiology and biotechnology Vol.23 No.11
In mice, supplementation of t10,c12 conjugated linoleic acid (CLA) increases liver mass and hepatic steatosis via increasing uptake of fatty acids released from adipose tissues. However, the effects of t10,c12 CLA on hepatic lipid synthesis and the associated mechanisms are largely unknown. Thus, we tested the hypothesis that gut microbiota-producing t10,c12 CLA would induce de novo lipogenesis and triglyceride (TG) synthesis in HepG2 cells, promoting lipid accumulation. It was found that treatment with t10,c12 CLA (100 μM) for 72 h increased neutral lipid accumulation via enhanced incorporation of acetate, palmitate, oleate, and 2- deoxyglucose into TG. Furthermore, treatment with t10,c12 CLA led to increased mRNA expression and protein levels of lipogenic genes including SREBP1, ACC1, FASN, ELOVL6, GPAT1, and DGAT1, presenting potential mechanisms by which CLA may increase lipid deposition. Most strikingly, t10,c12 CLA treatment for 3 h increased phosphorylation of mTOR, S6K, and S6. Taken together, gut microbiota-producing t10,c12 CLA activates hepatic de novo lipogenesis and TG synthesis through activation of the mTOR/SREBP1 pathway, with consequent lipid accumulation in HepG2 cells.
Wu, You-Sheng,Bao, Deng-Ke,Dai, Jing-Yao,Chen, Cheng,Zhang, Hong-Xin,Yang, YeFa,Xing, Jin-Liang,Huang, Xiao-Jun,Wan, Shao-Gui Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.3
Aberrant expression of genes in de novo lipogenesis (DNL) pathway were associated with various cancers, including hepatocellular carcinoma (HCC). Single nucleotide polymorphisms (SNPs) of DNL genes have been reported to be associated with prognosis of some malignancies. However, the effects of SNPs in DNL genes on overall survival of HCC patients receiving transarterial chemoembolization (TACE) treatment are still unknown. In present study, nine SNPs in three genes (ACLY, ACACA and FASN) in DNL pathway were genotyped using the Sequenom iPLEX genotyping system in a hospital-based cohort with 419 HCC patients treated with TACE, and their associations with HCC overall survival were evaluated by Cox proportional hazard regression analysis under three genetic models (additive, dominant and recessive). Although we did not find any significant results in total analysis (all p>0.05), our stratified data showed that SNP rs9912300 in ACLY gene was significantly associated with overall survival of HCC patients with lower AFP level and SNP rs11871275 in ACACA gene was significantly associated with overall survival of HCC patients with higher AFP level. We further identified the significant interactions between AFP level and SNP rs9912300 or rs11871275 in the joint analysis. Conclusively, our data suggest that genetic variations in genes of DNL pathway may be a potential biomarker for predicting clinical outcome of HCC patients treated with TACE.
Jin, Xin,Zhang, Ke-Jin,Guo, Xu,Myers, Ronald,Ye, Zhong,Zhang, Zhi-Pei,Li, Xiao-Fei,Yang, Hu-Shan,Xing, Jin-Liang Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.17
Over-expression of de novo lipogenesis (DNL) genes is associated with the prognosis of various types of cancers. However, the effects of single nucleotide polymorphisms (SNPs) in these genes on recurrence and survival of non-small cell lung cancer (NSCLC) patients after surgery are still unknown. In this study, a total of 500 NSCLC patients who underwent surgery treatment were included. Eight SNPs in 3 genes (ACACA, FASN and ACLY) of the DNL pathway were examined using the Sequenom iPLEX genotyping system. Multivariate Cox proportional hazards regression and Kaplan-Meier curves were used to analyze the association of SNPs with patient survival and tumour recurrence. We found that two SNPs in the FASN gene were significantly associated with the recurrence of NSCLC. SNP rs4246444 had a significant association with lung cancer recurrence under additive model (hazard ratio [HR], 0.82; 95% confidence interval [95%CI], 0.67-1.00; p=0.05). Under the dominant model, rs4485435 exhibited a significant association with recurrence (HR, 0.75; 95%CI, 0.56-1.01; p=0.05). Additionally, SNP rs9912300 in ACLY gene was significantly associated with overall survival in lung cancer patients (HR, 1.41; 95%CI, 1.02-1.94, p=0.04) under the dominant model. Further cumulative effect analysis showed moderate dose-dependent effects of unfavorable SNPs on both survival and recurrence. Our data suggest that the SNPs in DNL genes may serve as independent prognostic markers for NSCLC patients after surgery.
Antiobesity Effect of Tricin, a Methylated Cereal Flavone, in High-Fat-Diet-Induced Obese Mice
Lee, Dabeen,Imm, Jee-Young American Chemical Society 2018 Journal of agricultural and food chemistry Vol.66 No.38
<P>The antiobesity potential of tricin, a methylated cereal flavonoid, was examined using a high-fat-diet-induced obese mice model. The body weight (<I>P</I> < 0.01) and body fat mass (<I>P</I> < 0.05) were significantly decreased in the high-dose tricin supplementation group (TH: 200 mg/kg diet) in comparison to the high fat diet control group (CON) after a 12-week feeding trial. The serum (60.9 ± 2.09 mg/dL) and hepatic triglyceride levels (45.3 ± 4.42 nmol/mg protein) in the TH group were significantly decreased in comparison to the CON group (78.3 ± 5.09 mg/dL, 76.3 ± 8.10 nmol/mg protein), respectively. This antiobesity effect was attributed to a decrease in the expression of lipogenic markers crucial for fat synthesis in the liver (fatty acid synthase, stearoyl-CoA desaturase 1, elongation of long-chain fatty acids family member 6, glycerol-3-phosphate acyltransferase, and diglyceride acyltransferase) and suppressed expression of transcription factors associated with adipocyte differentiation (peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α). These lipid-lowering effects are mediated by the activation of adenosine 5′-monophosphate-activated protein kinase.</P> [FIG OMISSION]</BR>