Consequences of Lipid Droplet Coat Protein Downregulation in Liver Cells: Abnormal Lipid Droplet Metabolism and Induction of Insulin Resistance

Background: CCl4 acute liver injury (ALI) is a classical model for experimental research. However, there are few reports involved in the fundamental research of CCl4-induced ALI Ligustri Lucidi Fructus (LLF) are and its prescription have been used to treat hepatitis illness clinically. LLF and its active ingredients displayed anti-hepatitis effects, but the mechanism of function has not been fully clarified Objective: To investigate the proteomic analysis of CCl4-induced ALI, and examine the effects of active total glycosides (TG) from LLF on ALI of mice4, including histopathological survey and proteomic changes of liver tissues, and delineate the possible underlying mechanism. Methods: CCl4 was used to produce ALI mice model. The model mice were intragastrically administrated with TG and the liver his-topathological changes of mice were examined. At the end of test, mice liver samples were collected, after protein denaturation, re-duction, desalination and enzymatic hydrolysis, identification was carried out by nano LC-ESI-OrbiTrap MS/MS technology. The data was processed by Maxquant software. The differentially-expressed proteins were screened and identified, and their biological information was also analyzed based on GO and KEGG analysis. Key protein expression was validated by Western blot analysis Results: A total of 705 differentially-expressed proteins were identified during the normal, model and administration group. 9 signifi-cant differential proteins were focused based on analysis. Liver protein expression changes of CCl4-induced ALI mice were mainly involved in several important signal channels, namely FoxO signaling pathway, autophagy-animal, insulin signaling pathway. TG has anti-liver damnification effect in ALI mice, the mechanism of which is related to FoxO1 and autophagy pathways Conclusion: CCl4 inhibited expression of insulin-Like growth factor 1 (Igf1) and 3-phosphoinositide-dependent protein kinase 1 (Pdpk1) in liver cells and induced insulin resistance, thus interfered with mitochondrial autophagy and regeneration of liver cells and the metabolism of glucose and lipid, and caused hepatic necrosis in mice. TG resisted liver injury in mice. TG adjusted the expression level of key proteins Igf1 and Pdpk1 after liver injury and improved insulin resistance, thus promoted autophagy and resisted the liver damage

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The lipid droplet coat protein perilipin 5 also localizes to muscle mitochondria

Histochemistry and Cell Biology ◽

10.1007/s00418-011-0888-x ◽

2011 ◽

Vol 137 (2) ◽

pp. 205-216 ◽

Cited By ~ 109

Author(s):

Madeleen Bosma ◽

Ronnie Minnaard ◽

Lauren M. Sparks ◽

Gert Schaart ◽

Mario Losen ◽

...

Keyword(s):

Coat Protein ◽

Lipid Droplet ◽

Muscle Mitochondria ◽

Perilipin 5

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Abstract 610: Ineffective Suppression of Adipocyte Lipolysis in Metabolic Syndrome: An in vivo Test for Adipocyte Insulin Resistance

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.610 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Jennifer L Ford ◽

Raymond C Boston ◽

Rachel E Walker ◽

Gregory C Shearer

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Insulin Sensitivity ◽

Lipid Droplet ◽

Minimal Model ◽

Initial Rate ◽

Intravenous Glucose Tolerance Test ◽

Intravenous Glucose ◽

In Vivo Test

Background: Insulin resistance is a major contributor to metabolic syndrome, disrupting both glucose and non-esterified fatty acid (NEFA) dynamics through ineffective glucose clearance and decreased suppression of lipid droplet lipolysis. The minimal model of glucose dynamics is used for glycemic insulin sensitivity however it does not measure adipocyte insulin sensitivity, the primary determinant of plasma NEFA. An in-vivo approach to measuring adipocyte insulin sensitivity using NEFA is employed, comparing healthy and metabolic syndrome subjects. Both the models are employed to estimate insulin sensitivity and validate the NEFA approach. Objective: To test the use of NEFA kinetics to measure adipocyte insulin sensitivity compared to the glucose minimal model. Approach and results: Metabolic syndrome (n=56) and optimally healthy (n=14) subjects underwent a frequently sampled intravenous glucose tolerance test, and plasma analyzed for insulin, glucose, and NEFA. Insulin sensitivity ( S I ) and glucose effectiveness ( S G ) were calculated from the glucose minimal model. S I was 1.7 (mU/L) -1 min -1 and 0.40 (mU/L) -1 /min -1 and S G was 0.027 min -1 and 0.017 min -1 for the healthy and metabolic syndrome groups, respectively, indicating substantial glycemic insulin resistance in the latter. A model using glucose as the driver for NEFA kinetics was then applied. We found the initial rate of NEFA utilization by tissues (NU) was less, but the threshold glucose (tG) and glucose concentration required for a unit change in lipolysis inhibition ( G i ) were greater in metabolic syndrome verses healthy (NU: 0.050[0.045, 0.057] vs. 0.068[0.054, 0.086] p=0.03; tG: 6.7[6.2, 7.2] vs. 5.0[4.3, 5.9] p=0.001; G i : 0.30[0.25, 0.35] vs. 0.17[0.07, 0.27] p=0.02). No differences were found in initial rate of NEFA production or glucose utilization. Conclusion: Our results indicate that suppression of lipid-droplet lipolysis requires greater stimulus in metabolic syndrome compared to insulin sensitive adipocytes. Further, the rate of NEFA removal is less in metabolic syndrome. These results reveal components of insulin sensitivity not demonstrated by the glucose model. The NEFA model provides a measurement of adipocyte insulin sensitivity not captured by glycemic indices.

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Resistin and adenylyl cyclase-associated protein 1 (CAP1) regulate the expression of genes related to insulin resistance in BNL CL.2 mouse liver cells

Data in Brief ◽

10.1016/j.dib.2019.104112 ◽

2019 ◽

Vol 25 ◽

pp. 104112 ◽

Cited By ~ 1

Author(s):

Dimiter Avtanski ◽

Karin Chen ◽

Leonid Poretsky

Keyword(s):

Insulin Resistance ◽

Adenylyl Cyclase ◽

Mouse Liver ◽

Liver Cells ◽

Expression Of Genes

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Lipid-Induced Endoplasmic Reticulum Stress in Liver Cells Results in Two Distinct Outcomes: Adaptation with Enhanced Insulin Signaling or Insulin Resistance

Endocrinology ◽

10.1210/en.2011-1881 ◽

2012 ◽

Vol 153 (5) ◽

pp. 2164-2177 ◽

Cited By ~ 49

Author(s):

Caroline S. Achard ◽

D. Ross Laybutt

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Insulin Signaling ◽

Hepg2 Cells ◽

Glycogen Synthesis ◽

Liver Cells ◽

Dependent Manner ◽

Akt Phosphorylation ◽

High Level

Chronically elevated fatty acids contribute to insulin resistance through poorly defined mechanisms. Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been implicated in lipid-induced insulin resistance. However, the UPR is also a fundamental mechanism required for cell adaptation and survival. We aimed to distinguish the adaptive and deleterious effects of lipid-induced ER stress on hepatic insulin action. Exposure of human hepatoma HepG2 cells or mouse primary hepatocytes to the saturated fatty acid palmitate enhanced ER stress in a dose-dependent manner. Strikingly, exposure of HepG2 cells to prolonged mild ER stress activation induced by low levels of thapsigargin, tunicamycin, or palmitate augmented insulin-stimulated Akt phosphorylation. This chronic mild ER stress subsequently attenuated the acute stress response to high-level palmitate challenge. In contrast, exposure of HepG2 cells or hepatocytes to severe ER stress induced by high levels of palmitate was associated with reduced insulin-stimulated Akt phosphorylation and glycogen synthesis, as well as increased expression of glucose-6-phosphatase. Attenuation of ER stress using chemical chaperones (trimethylamine N-oxide or tauroursodeoxycholic acid) partially protected against the lipid-induced changes in insulin signaling. These findings in liver cells suggest that mild ER stress associated with chronic low-level palmitate exposure induces an adaptive UPR that enhances insulin signaling and protects against the effects of high-level palmitate. However, in the absence of chronic adaptation, severe ER stress induced by high-level palmitate exposure induces deleterious UPR signaling that contributes to insulin resistance and metabolic dysregulation.

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Polychlorinated biphenyls exposure-induced insulin resistance is mediated by lipid droplet enlargement through Fsp27

Archives of Toxicology ◽

10.1007/s00204-016-1889-2 ◽

2016 ◽

Vol 91 (6) ◽

pp. 2353-2363 ◽

Cited By ~ 9

Author(s):

Hye Young Kim ◽

Woo Young Kwon ◽

Yeon A. Kim ◽

Yoo Jin Oh ◽

Seung Hee Yoo ◽

...

Keyword(s):

Insulin Resistance ◽

Polychlorinated Biphenyls ◽

Lipid Droplet

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Regulation of MicroRNA 183 by Cyclooxygenase 2 in Liver Is DEAD-Box Helicase p68 (DDX5) Dependent: Role in Insulin Signaling

Molecular and Cellular Biology ◽

10.1128/mcb.00198-15 ◽

2015 ◽

Vol 35 (14) ◽

pp. 2554-2567 ◽

Cited By ~ 18

Author(s):

Omar Motiño ◽

Daniel E. Francés ◽

Rafael Mayoral ◽

Luis Castro-Sánchez ◽

María Fernández-Velasco ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Liver Cells ◽

Mirna Regulation ◽

Phosphatidylinositol 3 Kinase ◽

Mirna Processing ◽

Dead Box ◽

Physiological Processes ◽

Enzymatic Function ◽

Cox 2

Cyclooxygenase (COX) catalyzes the first step in prostanoid biosynthesis and exists as two isoforms. COX-1 is a constitutive enzyme involved in physiological processes, whereas COX-2 is induced by a variety of stimuli. MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. Although it is known that COX-2 expression is regulated by miRNAs, there are no data regarding COX-2 involvement in miRNA regulation. Considering our previous results showing that COX-2 expression in hepatocytes protects against insulin resistance, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs implicated in insulin signaling in liver cells. Our results provide evidence of the molecular basis for a novel function of COX-2 in miRNA processing. COX-2 represses miRNA 23b (miR-23b), miR-146b, and miR-183 expression in liver cells by increasing the level of DEAD-box helicase p68 (DDX5) through phosphatidylinositol 3-kinase (PI3K)/p300 signaling and by modulating the enzymatic function of the Drosha (RNase type III) complex through its physical association with DDX5. The decrease of miR-183 expression promotes protection against insulin resistance by increasing insulin receptor substrate 1 (IRS1) levels. These results indicate that the modulation of miRNA processing by COX-2 is a key event in insulin signaling in liver and has potential clinical implications for the management of various hepatic dysfunctions.

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