EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Yasi Mo,Yong Wu,Xin Li,Hui Rao,Xianxiang Tian,Danni Wu,Zhenpeng Qiu,Guohua Zheng,Junjie Hu
Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies worldwide. Inhibition of the lipogenic enzymes involved in hepatic de novo lipogenesis can both effectively restrain proliferation of HCC cells in vitro and reduce the risk of hepatocarcinogenesis in vivo . Although a natural coumarin derivative osthole shows efficacy in suppressing cell proliferation and inducing apoptosis in cultured hepatoma cells and HCC xenograft tumors, the molecular mechanism by which osthole delays hepatocellular malignant transformation during lipogenesis-driven hepatocarcinogenesis remains unknown. Here, we evaluate the efficacy of osthole in a rapid HCC mouse model featuring excessive levels of hepatic steatosis established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Moreover, human hepatoma cell lines were employed for in vitro assessment. Hematoxylin and eosin staining , immunoblotting and immunohistochemistry were applied for mechanistic investigations. The results revealed that if osthole was administered in the early stage of AKT/c-Met-driven HCC, it led to disease stabilization. Moreover, osthole alleviated hepatic steatosis in the AKT/c-Met mice. Further evidence at the molecular level suggested that osthole reduced the expression of phosphor-extracellular signal-regulated kinase 1/2 (ERK1/2), proliferating cell nuclear antigen (PCNA) and Ki67 in livers of the AKT/c-Met mice. Mechanically, osthole efficiently repressed the phospho-AKT (Thr308) / ribosomal protein S6 (RPS6) / fatty acid synthase (FASN) signaling both in mice and in vitro . Altogether, this study suggests that osthole exerts its antilipogenic and antiproliferative efficacy by suppressing the AKT/FASN axis and ERK phosphorylation, which contributes to its capacity to delay hepatocarcinogenesis.
研究领域:
癌症研究
·
分子生物学
·
药理学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aquaculture Reports
·
2022
·
IF 3.385
Jia Xu,Menglin Shi,Guilun He,Shuyan Chi,Shuang Zhang,Junming Cao,Beiping Tan,Shiwei Xie
As antibiotics-treated animal models provide good insights into the potential causes of the microbiota-dependent changes, we explored the effects of microbiota perturbation driven by a mixture of antibiotics on lipid metabolism and lipid deposition in the liver of hybrid grouper ( Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) fed a bile acid diet in this study. Ninety groupers were randomly fed a bile acids diet (SBD) or a bile acids diet supplemented with antibiotics mixture (ASBD) for a short-term period. The results showed that ASBD treatment significantly decreased the level of hepatic lipid droplets, the content of hepatic triglycerides and total cholesterol, and serum low-density lipoprotein cholesterol, while significantly increasing the content of high-density lipoprotein cholesterol, compared to the SBD group. The fish fed ASBD showed significantly enhanced activities of lipolytic enzymes, expression of lipolytic proteins and transcriptional factors genes, whereas significantly reduced the expression of lipogenic transcriptional factor genes. In addition, the antibiotics treatment significantly increased the abundance of Bacteroidetes, while non-significantly decreasing the Firmicutes/Bacteroidetes ratio ( p = 0.061). No significant shifts were observed in the α-diversity indices in SBD and ASBD groups, although the structures and potential functions of the intestinal microbiota were clearly separated. In conclusion, the antibiotics treatment reduced the lipid deposition and altered lipid metabolism via mainly enhancing hepatic lipolysis and slightly reducing hepatic lipogenesis.
研究领域:
水产养殖
·
微生物学
·
营养学
·
生理学
✓ 已验证
产品关联
DOI
高影响因子
Cell Metabolism
·
2024
·
IF 27.7
Yilie Liao,Qishan Chen,Lei Liu,Haipeng Huang,Jingyun Sun,Xiaojie Bai,Chenchen Jin,Honghao Li,Fangfang Sun,Xia Xiao,Yahong Zhang,Jia Li,Weiping Han,Suneng Fu
Increased de novo lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, ex vivo tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. In vivo , dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.
研究领域:
代谢
·
营养
·
肝病学
·
肥胖研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Haining Du,Lili Cui,Xinyi Zhao,Ziteng Yu,Tianyue He,Boya Zhang,Xingpei Fan,Meimei Zhao,Ruijiao Zhu,Ziyi Zhang,Mengcong Li,Jiaxin Li,Yuri Oh,Ning Gu
Butylparaben, a common preservative, is widely used in food, pharmaceuticals and personal care products. Epidemiological studies have revealed the close relationship between butylparaben and diabetes; however the mechanisms of action remain unclear. In this study, we administered butylparaben orally to mice and observed that exposure to butylparaben induced glucose intolerance and hyperlipidemia. RNA sequencing results demonstrated that the enrichment of differentially expressed genes was associated with lipid metabolism, bile acid metabolism, and inflammatory response. Western blot results further validated that butylparaben promoted hepatic lipogenesis, inflammation, gluconeogenesis, and insulin resistance through the inhibition of the farnesoid X receptor (FXR) pathway. The FXR agonists alleviated the butylparaben-induced metabolic disorders. Moreover, 16 S rRNA sequencing showed that butylparaben reduced the abundance of Bacteroidetes , S24–7, Lactobacillus, and Streptococcus , and elevated the Firmicutes / Bacteroidetes ratio. The gut microbiota dysbiosis caused by butylparaben led to decreased bile acids (BAs) production and increased inflammatory response, which further induced hepatic glycolipid metabolic disorders. Our results also demonstrated that probiotics attenuated butylparaben-induced disturbances of the gut microbiota and hepatic metabolism. Taken collectively, the findings reveal that butylparaben induced gut microbiota dysbiosis and decreased BAs production, which further inhibited FXR signaling, ultimately contributing to glycolipid metabolic disorders in the liver.
研究领域:
药理学
·
代谢学
·
微生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）