Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner

Shao, Wei; Machamer, Carolyn E.; Espenshade, Peter J.

doi:10.1194/jlr.m069583

Cited by 59 publications

(33 citation statements)

References 43 publications

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“…To further investigate the involvement of SCAP ubiquitination in the effects of RNF145 on SREBP processing, we reconstituted SCAP -knockout HEK293 cells ( Shao et al, 2016 ) with either WT SCAP or lysine-mutant SCAP (K454R, K466R). Under sterol depletion conditions, we found that Rnf145 expression was able to inhibit SREBP-2 processing in SCAP -knockout cells reconstituted with WT SCAP, but not in those reconstituted with lysine-mutant SCAP ( Figure 6D ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

Zhang

Rajbhandari

Priest

et al. 2017

eLife

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Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.

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Section: Resultsmentioning

confidence: 99%

Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

Zhang

Rajbhandari

Priest

et al. 2017

eLife

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“…7 ). The source of lipids for this lipid accumulation is unclear but de novo lipogenesis genes, such as FASN and ACC, are not regulated (either up or down) by FS in lipid-containing FBS suggesting other lipogenesis regulators, such as ChREBP or LXRα, are not involved 26 . SCAP/SREBP inhibition does not appear to be involved in FS action in these conditions as SREBP target genes were not regulated and lipid levels were not reduced.…”

Section: Discussionmentioning

confidence: 99%

Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer

et al. 2018

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Given the dependence of cancers on de novo lipogenesis, we tested the effect of fatostatin, a small molecule thought to target this pathway by blocking activation of SREBP transcription factors, in breast cancer cell lines and xenograft tumors. We found that estrogen receptor (ER) positive cells were more sensitive to fatostatin than ER negative cells and responded with cell cycle arrest and apoptosis. Surprisingly, we found that rather than inhibiting lipogenesis, fatostatin caused an accumulation of lipids as a response to endoplasmic reticulum stress rather than inhibition of SREBP activity. In particular, ceramide and dihydroceramide levels increased and contributed to the apoptotic effects of fatostatin. In addition, an accumulation of triacylglycerides (TAGs), particularly those containing polyunsaturated fatty acids (PUFAs), was also observed as a result of elevated diacylglycerol transferase activity. Blocking PUFA-TAG production enhanced the apoptotic effect of fatostatin, suggesting that these lipids play a protective role and limit fatostatin response. Together, these findings indicate that the ability of breast cancer cells to respond to fatostatin depends on induction of endoplasmic reticulum stress and subsequent ceramide accumulation, and that limiting production of PUFA-TAGs may be therapeutically beneficial in specific tumor subtypes.

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“…Another agent is fatostatin, that interacts with Scap, blocks ER-Golgi translocation of SREBP and decreases blood glucose and liver steatosis in obese ob/ob mice. 86 Fatostatin also has antitumor properties and inhibits cell growth. 87 Other natural compounds, including and rographolide and anhydroicaritin, ameliorate obesity, insulin resistance, liver steatosis and hyperlipemia via suppression of SREBP activation.…”

Section: Srebps In Liver Diseasementioning

confidence: 99%

Role of SREBPs in Liver Diseases: A Mini-review

Moslehi¹,

Hamidizad²

2018

Journal of Clinical and Translational Hepatology

122

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Sterol regulator element binding proteins (SREBPs) are a family of transcription factors involved in the biogenesis of cholesterol, fatty acids and triglycerides. They also regulate physiological functions of many organs, such as thyroid, brain, heart, pancreas and hormone synthesis. Beside the physiological effects, SREBPs participate in some pathological processes, diabetes, endoplasmic reticulum stress, atherosclerosis and chronic kidney disease associated with SREBP expression changes. In the liver, SREBPs are involved in the pathogenesis of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatitis and hepatic cancer. There are several SREBP inhibitors that have potential for treating obesity, diabetes and cancer. This review assesses the recent findings about the roles of SREBPs in the physiology of organs’ function and pathogenesis of liver diseases.

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Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner

Cited by 59 publications

References 43 publications

Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer

Role of SREBPs in Liver Diseases: A Mini-review

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