A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP

Kamisuki, Shinji; Mao, Qian; Abu-Elheiga, Lutfi; Gu, Zhongwei; Kugimiya, Akira; Kwon, Young Joo; Shinohara, Tetsuji; Kawazoe, Yoshinori; Sato, Shin; Asakura, Koko; Choo, Hea Young Park; Sakai, Juro; Wakil, Salih J.; Uesugi, Motonari

doi:10.1016/j.chembiol.2009.07.007

Cited by 243 publications

(238 citation statements)

References 34 publications

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“…Mvd, a lipogenic enzyme, was downregulated in ob/ob mice receiving fatostatin treatment [53]. The expression of Pcsk9, associated with hypercholesterolemia, decreased after berberine treatment of HFD-induced obese mice [54].…”

Section: Discussionmentioning

confidence: 99%

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Wang

Yen

Cheng

et al. 2017

Food & Nutrition Research

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Obesity, the excessive accumulation of lipids in the body, is closely associated with many prevalent human disorders. Continued efforts to identify plant extracts that exhibit anti-obesity effects have drawn much attention. This study investigated whether a Polygala tenuifolia extract (PTE) possesses anti-obesity activity and how PTE may affect liver gene expression and gut microbiota. We used 3T3-L1 adipocytes and a high-fat diet–induced obese mouse model to determine the effects of PTE on lipid accumulation. Next-generation sequencing analysis of liver gene expression and gut microbiota profiles following PTE treatment were conducted to elucidate possible mechanisms. We found that treatment of fully differentiated 3T3-L1 adipocytes with PTE inhibited lipid accumulation in the cells through reducing lipid formation and triglyceride content and by increasing lipase activity. No cytotoxicity was observed from the PTE treatment. After 5 weeks of treatment with PTE, the increased body weight, elevated serum triglyceride content, and liver steatosis in the high-fat diet–induced obese mice were each reduced. Liver transcriptomic analysis revealed that expression of genes involved in lipid and cholesterol metabolism was significantly altered. The low-grade chronic inflammation of obesity caused by a high-fat diet was also decreased after PTE treatment. In addition, treatment with PTE improved the relatively low Bacteroidetes/Firmicutes ratio in the gut of high-fat diet–fed mice through enrichment of the Proteobacteria population and reduction of the Deferribacteres population. In conclusion, treatment with PTE inhibited lipid accumulation by inducing the expression of the master transcription factor PPARα, attenuated the low-grade chronic inflammation of obesity, and also altered gut microbiota profiles. These results indicate that PTE has the potential to be developed into an anti-obesity food supplement and therapy. Abbreviations: Abcg5: ATP-binding cassette subfamily G member 5; ALT: alanine aminotransferase; AMPK: adenosine monophosphate-activated protein kinase; AST: aspartate aminotransferase; B/F: Bacteroidetes to Firmicutes [ratio]; C/EBPα: CCAAT/enhancer-binding protein alpha; CR: creatinine; Cyp51: cytochrome P450 family 51; DMEM: Dulbecco’s modified Eagle’s medium; Fabp5: fatty acid-binding protein 5; FBS: fetal bovine serum; Fdps: farnesyl diphosphate synthase; Glc: Glucose; HFD: high-fat diet; GO: gene ontology; HPRT: hypoxanthine guanine phosphoribosyl transferase; IBMS: 3-isobutyl-1-methylxanthine; Idi1: isopentenyl-diphosphate delta isomerase 1; IL-1β: interleukin-1-beta; Lpin1: phosphatidic acid phosphohydrolase; LPS: lipopolysaccharide; Mvd: mevalonate diphosphate decarboxylase; ND: normal diet; OTU: operational taxonomic units; Pcsk9: proprotein convertase subtilisin/kexin 9; Pctp: phosphatidylcholine transfer protein; PPARα: peroxisome proliferator-activated receptor alpha; PPARγ: peroxisome proliferator-activated receptor gamma; PTE: Polygala tenuifolia extract; Saa1: serum amyloid A1; SD: ...

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Section: Discussionmentioning

confidence: 99%

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Wang

Yen

Cheng

et al. 2017

Food & Nutrition Research

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“…3D) in 1-LN and DU-145 prostate cancer cells stimulated with ␣ 2 M*. Previous studies of head and neck tumors have shown a correlation of high lactate levels with an increased incidence of metastasis (91 (Fig. 4, C and D).…”

Section: Elevated Glucose Uptake In Prostate Cancermentioning

confidence: 99%

“…6). Pretreatment of prostate cancer cells with inhibitors of PI 3-kinase/Akt/mTORC or fatty-acid synthase significantly reduced ␣ 2 M*/insulin-induced increased phosphatidylcholine synthesis from 1-[ 14 (91,92). Stimulation of prostate cancer cells with ␣ 2 M*, similar to insulin, up-regulated protein synthesis 2-3-fold in 1-LN, DU-145, and LnCap cells compared with buffer-treated controls, although pretreatment of cells with fatostatin A nearly abolished these effects (Fig.…”

Section: ␣ 2 M* and Insulin Increase The Incorporation Of 1-[ 14 C]acmentioning

confidence: 99%

Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

Misra

Pizzo

2015

Journal of Biological Chemistry

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Background: Ligation of cancer cell surface GRP78 by activated ␣ 2 -macroglobulin (␣ 2 M*) promotes proliferation and blocks apoptosis. Results: ␣ 2 M* treatment of prostate cancer cells enhances the Warburg effect and up-regulates lipid metabolism in an insulinlike manner. Conclusion: ␣ 2 M* exerts insulin-like effects on prostate cancer cells. Significance: Targeting cell surface GRP78-dependent cancer cell regulation, such as by antibodies, offers a unique potential therapeutic approach.

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“…SREBP is an important transcription factor that activates cholesterol-synthesizing genes. Small molecule inhibitors of SREBP are highly desirable due to their potential to treat atherosclerosis (Kamisuki et al, 2009). ER-b selective agonists markedly (6-to 7-fold) decreased SREBP in white adipose tissue of animals fed with a high-fat diet compared with vehicletreated animals.…”

Section: Er-b Selective Ligands As Novel Therapeutics For Obesity Andmentioning

confidence: 99%

Role of Nuclear Receptors in Lipid Dysfunction and Obesity-Related Diseases

et al. 2012

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This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 12 meeting in San Diego, CA. The presentations discussed the roles of a number of nuclear receptors in regulating glucose and lipid homeostasis, the pathophysiology of obesity-related disease states, and the promise associated with targeting their activities to treat these diseases. While many of these receptors (in particular, constitutive androstane receptor and pregnane X receptor) and their target enzymes have been thought of as regulators of drug and xenobiotic metabolism, this symposium highlighted the advances made in our understanding of the endogenous functions of these receptors. Similarly, as we gain a better understanding of the mechanisms underlying bile acid signaling pathways in the regulation of body weight and glucose homeostasis, we see the importance of using complementary approaches to elucidate this fascinating network of pathways. The observation that some receptors, like the farnesoid X receptor, can function in a tissue-specific manner via well defined mechanisms has important clinical implications, particularly in the treatment of liver diseases. Finally, the novel findings that agents that selectively activate estrogen receptor b can effectively inhibit weight gain in a high-fat diet model of obesity identifies a new role for this member of the steroid superfamily. Taken together, the significant findings reported during this symposium illustrate the promise associated with targeting a number of nuclear receptors for the development of new therapies to treat obesity and other metabolic disorders.

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A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP

Cited by 243 publications

References 34 publications

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

Role of Nuclear Receptors in Lipid Dysfunction and Obesity-Related Diseases

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