Endoplasmic reticulum stress leads to lipid accumulation through upregulation of SREBP-1c in normal hepatic and hepatoma cells

Fang, Dian‐Liang; Wan, Ying; Shen, Wei; Cao, Jie; Sun, Zhong-xin; Yu, Huihong; Zhang, Qin; Cheng, Wenhui; Chen, Juan; Niu, Bo

doi:10.1007/s11010-013-1694-7

Cited by 98 publications

(57 citation statements)

References 28 publications

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“…Liver index and our histological data (H&E and oil red O staining) showed that ER stress induction by TM challenge leads to severe steatosis and hepatocytes ballooning. These results were consistent with several previously published studies (26,27); however, amygdalin administration before ER stress induction was unable to decrease lipid accumulation in the hepatic cells. Our pervious study reported that naltrexone attenuated ER stress induced liver steatosis (28).…”

Section: Effect Of Amygdalin On the Serum Lipids Levelssupporting

confidence: 94%

The Effect of Amygdalin on Endoplasmic Reticulum (ER) Stress Induced Hepatic Steatosis in Mice

Moslehi

Farahabadi

Chavoshzadeh

et al. 2018

MJMS

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Section: Effect Of Amygdalin On the Serum Lipids Levelssupporting

confidence: 94%

The Effect of Amygdalin on Endoplasmic Reticulum (ER) Stress Induced Hepatic Steatosis in Mice

Moslehi

Farahabadi

Chavoshzadeh

et al. 2018

MJMS

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“…Pharmacologically induced ER stress in HepG2 cells increased the expression of SREBP-1c via cap-independent internal translation of SREBP-1c mRNA by hnRNP-A1 (103,104), which in turn activated fatty acid synthesis in L02 cells (105). ER stress also induced hepatic steatosis via increased expression of hepatic VLDL receptor (VLDLR) through direct binding of the ATF4 transcription factor to the VLDLR promoter region leading to accumulation of TG (106).…”

Section: Er Stress and Lipotoxicity In Peripheral Organsmentioning

confidence: 99%

The role of ER stress in lipid metabolism and lipotoxicity

Han

Kaufman

2016

Journal of Lipid Research

502

372

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extremely high Ca 2+ concentration (1), which is maintained by the active transport function of the sarco/ER calcium ATPase (SERCA) (2). Many ER chaperone proteins and enzymes depend on higher Ca 2+ levels to facilitate protein folding and maturation (3). Therefore, maintaining ER homeostasis is essential for proper protein production and cell function. Homeostasis in the ER is disrupted by a number of insults, including pharmacological perturbation, genetic mutation of ER chaperones or their client proteins, elevated expression of proteins that transit the endomembrane system, viral infection, alterations in Ca 2+ or redox status, and limited or excessive available nutrients such as lipids. The accumulation of unfolded or misfolded proteins in the ER lumen activates a set of intracellular signaling pathways known as the unfolded protein response (UPR) (4, 5). The UPR regulates the quantity of ER driven by synthesis of lipids (6) and protein components of the ER to accommodate fluctuating demands on protein folding and other ER functions in response to different physiological and pathological conditions.The ER is also the major site for the synthesis of sterols and phospholipids that constitute the bulk of the lipid components of all biological membranes. In addition, many enzymes and regulatory proteins involved in lipid metabolism reside in the ER. The ER, therefore, plays an essential role in controlling membrane lipid composition (7) and membrane lipid homeostasis in all cell types. Fat The endoplasmic reticulum (ER) is a central organelle where proteins destined for the cell surface and the endomembrane system enter the secretory pathway. Once inside the ER lumen, newly synthesized polypeptides fold into their three-dimensional structures, assemble into higher order multimeric complexes, and are subject to posttranslational modifications such as glycosylation, hydroxylation, lipidation, and disulfide formation. The ER contains an Abbreviations: ACC, acetyl-CoA carboxylase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, immunoglobulin heavy-chain binding protein; CHOP, C/EBP homologous protein; eIF2, eukaryotic translation initiation factor 2; ER, endoplasmic reticulum; ERAD, ER-associated degradation; FXR, farnesoid X receptor; GADD34, growth arrest and DNA damage-inducible protein 34; HFD, high-fat diet; HFrD, high-fructose diet; IRE1, inositol-requiring enzyme 1; 4-PBA, 4-phenylbutyric acid; PERK, the double-stranded RNAactivated protein kinase-like eukaryotic initiation factor 2 kinase; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; SERCA, sarco/ endoplasmic reticulum calcium ATPase; SFA, saturated fatty acid; S1P, serine protease site-1; S2P, metalloprotease site-2; SREBP, sterol regulatory element-binding protein; TUDCA, tauroursodeoxycholic acid; UPR, unfolded protein response; VLDLR, VLDL receptor; XBP1, X-box binding protein 1; Xbp1s, transcriptionally active form of X-box binding protein 1.

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“…LXRs induce the expression of SREBP1c, a master regulator of lipid and cholesterol metabolism (51,54), and mediate lipid accumulation in hepatocytes, as can be observed by oil red O staining (55,56). Employing this methodology, we treated uninfected Huh7.5.1 and Huh7-25 cells with compounds and then stained them with oil red O to observe intracellular lipid accumulation.…”

Section: Molecular Interaction Of Neob With Lxrs Is Correlated With Tmentioning

confidence: 99%

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

Nakajima

Watashi

Ohashi

et al. 2016

J Virol

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Cell culture systems reproducing virus replication can serve as unique models for the discovery of novel bioactive molecules. Here, using a hepatitis C virus (HCV) cell culture system, we identified neoechinulin B (NeoB), a fungus-derived compound, as an inhibitor of the liver X receptor (LXR). NeoB was initially identified by chemical screening as a compound that impeded the production of infectious HCV. Genome-wide transcriptome analysis and reporter assays revealed that NeoB specifically inhibits LXR-mediated transcription. NeoB was also shown to interact directly with LXRs. Analysis of structural analogs suggested that the molecular interaction of NeoB with LXR correlated with the capacity to inactivate LXR-mediated transcription and to modulate lipid metabolism in hepatocytes. Our data strongly suggested that NeoB is a novel LXR antagonist. Analysis using NeoB as a bioprobe revealed that LXRs support HCV replication: LXR inactivation resulted in dispersion of double-membrane vesicles, putative viral replication sites. Indeed, cells treated with NeoB showed decreased replicative permissiveness for poliovirus, which also replicates in double-membrane vesicles, but not for dengue virus, which replicates via a distinct membrane compartment. Together, our data suggest that LXR-mediated transcription regulates the formation of virus-associated membrane compartments. Significantly, inhibition of LXRs by NeoB enhanced the activity of all known classes of anti-HCV agents, and NeoB showed especially strong synergy when combined with interferon or an HCV NS5A inhibitor. Thus, our chemical genetics analysis demonstrates the utility of the HCV cell culture system for identifying novel bioactive molecules and characterizing the virushost interaction machinery. IMPORTANCEHepatitis C virus (HCV) is highly dependent on host factors for efficient replication. In the present study, we used an HCV cell culture system to screen an uncharacterized chemical library. Our results identified neoechinulin B (NeoB) as a novel inhibitor of the liver X receptor (LXR). NeoB inhibited the induction of LXR-regulated genes and altered lipid metabolism. Intriguingly, our results indicated that LXRs are critical to the process of HCV replication: LXR inactivation by NeoB disrupted double-membrane vesicles, putative sites of viral replication. Moreover, NeoB augmented the antiviral activity of all known classes of currently approved anti-HCV agents without increasing cytotoxicity. Thus, our strategy directly links the identification of novel bioactive compounds to basic virology and the development of new antiviral agents.

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Endoplasmic reticulum stress leads to lipid accumulation through upregulation of SREBP-1c in normal hepatic and hepatoma cells

Cited by 98 publications

References 28 publications

The Effect of Amygdalin on Endoplasmic Reticulum (ER) Stress Induced Hepatic Steatosis in Mice

The Effect of Amygdalin on Endoplasmic Reticulum (ER) Stress Induced Hepatic Steatosis in Mice

The role of ER stress in lipid metabolism and lipotoxicity

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

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