Discovery of an insulin‐induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element‐binding protein–mediated lipogenesis

Jiang, Shi-You; Yang, Xinglin; Yang, Zimo; Li, Jue-Wan; Xu, Meng-Qiang; Qu, Yuanzhi; Tang, Jinshan; Li, Yunfeng; Wang, Liguo; Shao, Yiwen; Meng, Xiangjun; Hu, Huili; Song, Bao-Liang; Rao, Yu; Qi, Wei

doi:10.1002/hep.32381

Cited by 33 publications

(20 citation statements)

References 49 publications

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“…SREBPs are membrane-bound transcription factors that regulate the expression of many genes involved in cholesterol biosynthesis (17). SREBPs are of the basic helix-loop-helix leucine zipper (bHLH) family of DNA binding proteins that sense the amount of cholesterol in cell membranes and help maintain the negative feedback control of cholesterol homeostasis (18). Normally in the presence of excess cholesterol SREBPs are sequestered in the endoplasmic reticulum where they are bound to an escort protein: SREP cleavageactivating protein (SCAP) and the ER-resident protein Insig.…”

Section: Discussionmentioning

confidence: 99%

“…Transcriptional activation results in increased LDL internalization via LDLr and the increased cytosolic cholesterol inhibits activation of the SREBP through negative feedback. Many studies have shown the importance of the SREBP-pathway for cellular cholesterol homeostasis in diseases such as Familial hypercholesterolemia, Niemann-Pick disease C, Tangier disease, and nonalcoholic steatohepatitis (6,18). Two different genes encode three SREBP isoforms; they are SREBP-1a, SREBP-1c, and SREBP-2 (20).…”

Section: Discussionmentioning

confidence: 99%

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The effects of LDL cholesterol and pitavastatin treatment on fibroblast migration, SREBP-2, and LDLr expression

Telgenhoff

Prajapati

2022

biolsciences

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Most non-healing wounds show a lack of cell migration contributing to chronic inflammation and infection. Cholesterol levels in the blood may have an impact on cell migration, as migrating cells demonstrate a need for cholesterol in order to synthesize additional cell membranes. Statins are a popular drug used for lowering blood cholesterol by competitive inhibition of HMG CoA reductase, a pivotal step in the cholesterol synthesis pathway. In this study, we examined the effects of low-density lipoprotein (LDL) and statin treatment on fibroblasts in vitro. A cholesterol ELISA was utilized to examine cholesterol levels in cultured fibroblasts following treatment with pitavastatin or LDL. A scratch-test assay was performed to examine fibroblast migration following treatment in addition to the MTT cell proliferation assay. Western blot analysis was used to examine the cholesterol signalling protein SREBP-2 and LDLr expression in treated cells. LDL treatment enhanced cell proliferation and migration, while both were inhibited by pitavastatin. Pitavastatin increased both SREBP-2 and LDLr expression in treated cells compared to LDL and vehicle control treatments. These results indicate pitavastatin inhibits cell migration and the cellular response is to increase cholesterol levels to make up for the inhibition of cholesterol synthesis though the mevalonate pathway. This could have significant effects on cell migration and wound healing in vivo for patients with inhibited wound healing responses on statin therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The effects of LDL cholesterol and pitavastatin treatment on fibroblast migration, SREBP-2, and LDLr expression

Telgenhoff

Prajapati

2022

biolsciences

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“…Compared to the control group, expression of fibrosis-related genes, such as collagen 1α1 (Col1a1), α-SMA (Acta2), and lysyl oxidase-like 2 (Loxl2) were elevated and prominent collagen accumulation was detected by picosirius red staining 90 . Recently, Song et al found 25-hydroxylanosterol (25-HL) has preventive and curative effects on NASH mice fed with HFFC diet 91 . Mechanistically, 25-HL binds to insulin-induced gene, promoting SCAR-SREBP retention in ER, thereby reducing the level of cholesterol and TG.…”

Section: Mouse Models Of Nafldmentioning

confidence: 99%

“…Mechanistically, 25-HL binds to insulin-induced gene, promoting SCAR-SREBP retention in ER, thereby reducing the level of cholesterol and TG. Another unique feature of this model is that HFFC diet-treated Ldlr -/- mice simultaneously induced the development NASH and atherosclerosis 91 . Therefore, this model has tremendous utility in developing new therapeutic targets as well as new drugs which ameliorate NASH and atherosclerosis in light of the fact that most NAFLD patients die from extrahepatic complications, such as atherosclerosis.…”

Section: Mouse Models Of Nafldmentioning

confidence: 99%

Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies

Fang¹,

Wang²,

Pan³

et al. 2022

Int. J. Biol. Sci.

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The prevalence of non-alcoholic fatty liver disease (NAFLD) increases year by year, and as a consequence, NAFLD has become one of the most prevalent liver diseases worldwide. Unfortunately, no pharmacotherapies for NAFLD have been approved by the United States Food and Drug Administration despite promising pre-clinical benefits; this situation highlights the urgent need to explore new therapeutic targets for NAFLD and for the discovery of effective therapeutic drugs. The mouse is one of the most commonly used models to study human disease and develop novel pharmacotherapies due to its small size, low-cost and ease in genetic engineering. Different mouse models are used to simulate various stages of NAFLD induced by dietary and/or genetic intervention. In this review, we summarize the newly described patho-mechanisms of NAFLD and review the preclinical mouse models of NAFLD (based on the method of induction) and appraises the use of these models in anti-NAFLD drug discovery. This article will provide a useful resource for researchers to select the appropriate model for research based on the research question being addressed.

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“…Hepatic inflammation is the main cause of liver injury, including NASH and its related diseases [ 6 , 7 ]. The pathogenesis of NASH is complex, and its occurrence and progression are regulated by hepatic lipid deposition, oxidative stress, insulin resistance, immune dysfunction, and apoptosis [ 8 , 9 , 10 , 11 ]. Emerging studies suggest that NAFLD-associated events significantly increase cancer mortality, cardiometabolic disease, and liver disease.…”

Section: Introductionmentioning

confidence: 99%

The STING in Non-Alcoholic Fatty Liver Diseases: Potential Therapeutic Targets in Inflammation-Carcinogenesis Pathway

Xing

Chen

et al. 2022

Pharmaceuticals

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Non-alcoholic fatty liver disease (NAFLD), an important chronic disease, is one of the major causes of high mortality and creates a substantial financial burden worldwide. The various immune cells in the liver, including macrophages, NK cells, dendritic cells, and the neutrophils involved in the innate immune response, trigger inflammation after recognizing the damage signaled from infection or injured cells and tissues. The stimulator of interferon genes (STING) is a critical molecule that binds to the cyclic dinucleotides (CDNs) generated by the cyclic GMP-AMP synthase (cGAS) to initiate the innate immune response against infection. Previous studies have demonstrated that the cGAS-STING pathway plays a critical role in inflammatory, auto-immune, and anti-viral immune responses. Recently, studies have focused on the role of STING in liver diseases, the results implying that alterations in its activity may be involved in the pathogenesis of liver disorders. Here, we summarize the function of STING in the development of NAFLD and present the current inhibitors and agonists targeting STING.

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Discovery of an insulin‐induced gene binding compound that ameliorates nonalcoholic steatohepatitis by inhibiting sterol regulatory element‐binding protein–mediated lipogenesis

Cited by 33 publications

References 49 publications

The effects of LDL cholesterol and pitavastatin treatment on fibroblast migration, SREBP-2, and LDLr expression

The effects of LDL cholesterol and pitavastatin treatment on fibroblast migration, SREBP-2, and LDLr expression

Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies

The STING in Non-Alcoholic Fatty Liver Diseases: Potential Therapeutic Targets in Inflammation-Carcinogenesis Pathway

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