The Effect of Fatty Acids in Hepatic Insulin Resistance - Part 1
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Hepatocyte, Cell Culture
DISEASE(S): Type 2 Diabetes Mellitus
SUBMITTER: 
Yaping Sun
LAB HEAD: Fuquan Yang
PROVIDER: PXD012065 | Pride | 2019-07-11
REPOSITORIES: Pride
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Project description:Monounsaturated fatty acid (MUFA) oleic acid (OA) has been reported to reverse saturated fatty acid palmitic acid (PA)-induced hepatic insulin resistance (IR). However, the detailed molecular mechanism remains elusive. In addition, previous research also showed that -3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA), exerted opposite effects to PA in muscle IR, but whether it plays the same role in hepatic IR and the possible mechanism involved needs to be further explored. Here, we confirmed that EPA reversed PA-induced IR in HepG2 cells and compared the proteome change after different free fatty acids (FFAs) treatments. For MUFA, 234 proteins were identified as differentially expressed proteins, and their functions were mainly related to response to stress and endogenous stimuli, lipid metabolic process and protein binding. For PUFA, the PA-induced expression change of 1326 proteins could be reversed by EPA and 415 of them were mitochondrial proteins, which covered most of the functional proteins in oxidative phosphorylation (OXPHOS) and tricarboxylic acid cycle (TCA). Mechanism study revealed that c-Jun and ROS played a role in OA- and EPA-reversed PA-induced IR, respectively. EPA or OA alleviated PA-induced abnormal ATP production, ROS generation, and calcium content. Importantly, H2O2-activated production of ROS increased the expression of c-Jun, further resulting in IR of HepG2 cells. Besides, we provided more feasible candidates as potential c-Jun-targeted “responders” for FFAs treatments. Taken together, we demonstrated that ROS/c-Jun is a common pathway to different FFAs-regulated IR in HepG2 cells.
2019-07-11 | PXD012066 | Pride
Project description:The cellular response to genotoxic stress is a well-characterized network of DNA surveillance pathways. The contribution of posttranscriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing irradiation (IR). Interestingly, more than 260 proteins showed increased binding to poly(A) RNA in IR-exposed cells and were comprised of many nucleolar proteins. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that DDX54 is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well defined class of pre-mRNAs which harbor introns with weak acceptor splice sites, as well as by protein-protein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Since DDX54 promotes survival after exposure to IR its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR.
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Project description:Maternal obesity during pregnancy leads to a pro-inflammatory milieu in the placenta. We conducted a global transcriptomic profiling in BeWo cells following palmitic acid (PA, 500 uM) and/or TNF-alpha (10 ng/ml) treatment for 24 h. Microarray analysis revealed that placental cytotrophoblasts increased expression of genes related to inflammation, stress response and immediate-early factors in response to plamitic acid, TNF-alpha or a combination of both. Our results suggest that fatty acids and inflammatory cytokines induce inflammation in placental cells via activation of JNK-Egr-1 signaling. global transcriptomic profiling in BeWo cells following palmitic acid (PA, 500 uM) and/or TNF-alpha (10 ng/ml) treatment for 24 h
2014-01-21 | E-GEOD-43685 | biostudies-arrayexpress
Project description:Saturated fatty acids (SFA) are widely thought to induce inflammation in adipose tissue (AT), while monounsaturated fatty acids (MUFA) are purported to have the opposite effect; however, it is unclear if individual SFA and MUFA behave similarly. Our goal was to examine adipocyte transcriptional networks regulated by individual SFA (palmitic acid, PA; stearic acid, SA) and MUFA (palmitoleic acid, PMA; oleic acid, OA). Global gene expression was examined in differentiated preadipocytes treated with either 250 M-NM-<M PA, SA, PMA, or OA for 48 hrs. Individual fatty acid treatments had significant effects on adipocyte gene expression. Functional analyses revealed that PA induced the TLR signalling pathway, while PMA had the opposite effect. SA and OA had similar effects, with increases in key metabolic pathways including mTOR and PPAR signalling, and a reduction in TLR signalling. Ccl5 was validated as a candidate gene that may mediate the differential inflammatory effects of SFA and MUFA in AT. Individual SFA and MUFA trigger distinct transcriptional responses in differentiated preadipocytes, with inflammatory and metabolic pathways particularly sensitive to these fatty acids. A total of 4 microarrays were run for each FA treatment. We experienced difficulties with the cRNA amplification for one replicate from the OA treated cells; therefore this treatment group only had an n=3. For each sample, 100 ng of total RNA was prepared for hybridization to Affymetrix Mouse Gene 1.1 ST array strips, according to the manufacturerM-bM-^@M-^Ys instructions (Affymetrix Inc., Fremont, CA, USA).
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Project description:Innate immunity serves as the primary defense against viral and microbial infections in humans. Among its components, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are well-characterized intracellular pattern-recognition proteins that trigger innate immune responses upon viral infection. However, the precise influence of cellular metabolites, especially fatty acids, on the regulation of RLR-mediated antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a crucial metabolite responsible for modulating antiviral infections. Mechanistically, PA induces the palmitoylation of MAVS, leading to MAVS aggregation and subsequent activation, thereby enhancing the innate immune response against viral infections. Functionally, the enzyme palmitoyl-transferase ZDHHC24 plays a key role in catalyzing the palmitoylation of MAVS at both C46 and C79 residues, thereby facilitating the transduction of RLR-mediated TBK1-IRF3-IFN signaling pathway, particularly under conditions of PA stimulation or high-fat diet feeding. Conversely, the absence of ZDHHC24 significantly attenuates virus-induced innate immune responses in both cells and mice. Moreover, APT2 counteracts with ZDHHC24 to de-palmitoylate MAVS, thus inhibiting the antiviral response. Consequently, inhibition of APT2 using compounds like ML349 effectively reverses MAVS palmitoylation and activation in response to antiviral infections. These findings underscore the critical role of PA and ZDHHC24 in regulating antiviral innate immunity through MAVS palmitoylation, and suggest potential therapeutic strategies for combating viral infections, such as enhancing PA intake or specifically targeting APT2.
2024-09-10 | PXD054077 | Pride
Project description:Metabolically healthy skeletal muscle is characterized by the ability to switch easily between glucose and fat oxidation, whereas loss of this ability seems to be related to insulin resistance. The aim of this study was to investigate whether different fatty acids (FAs) and the LXR ligand T0901317 affected metabolic switching in human skeletal muscle cells (myotubes). Pretreatment of myotubes with eicosapentaenoic acid (EPA) increased suppressibility, the ability of glucose to suppress FA oxidation, and metabolic flexibility, the ability to increase FA oxidation when changing from “fed” to “fasted” state. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was increased after pretreatment with EPA, linoleic acid (LA) and palmitic acid (PA). T0901317 counteracted the effect of EPA on suppressibility and adaptability, but did not affect these parameters alone. EPA itself accumulated less, however, EPA, LA, OA and T0901317 increased the number of lipid droplets (LDs) in myotubes, whereas LD size and mitochondria amount were independent of pretreatment. Microarray analysis showed that EPA regulated more genes than the other FAs. Some pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggests a possible favorable effect of EPA on skeletal muscle metabolic switching and glucose utilization. Keywords: Analysis of target gene regulation by using microarrays. Primary human myotubes, derived from 3 healthy, female donors, were preincubated with different fatty acids (oleic acid [OA], palmitic acid [PA], eicosapentaenoic acid [EPA] or linoleic acid [LA], each at 100 µM) or bovine serum albumin [BSA] (40 µM) for 24 h.
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Project description:Background: Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effects of PA on human chemotherapy resistant pancreatic cancer cells. Methods: Gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2 were used, along with a xenograft model of MIA PaCa-2 cells implanted in mice. Apoptosis was assessed by quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP. Differential expression of genes was identified using comparative DNA microarray analysis. Protein levels were determined by immunoblotting. Toxicology studies in vivo were assessed by detecting pathological changes in organs and liver enzyme profiles in plasma. Tumor tissues were analyzed by quantification of apoptotic bodies, qRT-PCR and immunoblotting. Principal Findings: PA induced endoplasmic reticulum (ER) stress in chemotherapy resistant pancreatic cancer cells through activation of heat shock response and unfolded protein response related genes, which further triggered apoptosis. The involvement of ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2M-NM-1. Moreover, 25 mg kgM-bM-^HM-^R1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis, ER stress related genes and proteins expression. Conclusions: Growth inhibition and induction of apoptosis by PA in chemotherapy resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. Pancreatic cancer cell line treated with pachymic acid vs. control (untreated)
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2010-05-19 | E-GEOD-13019 | biostudies-arrayexpress
Project description:Obesity-induced insulin resistance of the liver is characterised by increased gluconeogenesis, which contributes to elevated blood glucose levels in individuals with type 2 diabetes. Research into how fatty acids induce insulin resistance has commonly focused on the induction of insulin resistance. We hypothesise that by shifting focus to the reversal of an insulin resistant phenotype, novel insights can be made into the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered in parallel with restoration of palmitate-induced deregulation of glucose production using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075mM, 48h) with or without metformin (0.25mM) and sodium salicylate (2mM) in the final 24h of palmitate treatment, and effects on glucose production were determined. Microarray followed by gene set enrichment analysis was performed to investigate pathway regulation. A lipidomic analysis (HPLC-MS/MS) and measurement of secreted bile acids and cholesterol were performed. Reversal of palmitate-induced impairment of glucose production by metformin and sodium salicylate was characterised by down-regulated expression of metabolic pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. Total levels of intracellular and secreted cholesterol and bile acids were not different between impaired and restored glucose production. Total intracellular levels of diacylgycerol, triacylglycerol and cholesterol esters increased with palmitate (impaired glucose production), however, these were not further altered with metformin and sodium salicylate (restored glucose production). Six individual lipid species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. Widespread lipid metabolism changes induced by the reversal of palmitate-induced deregulation of glucose production with metformin and sodium salicylate were identified. While cholesterol and bile acid levels remained unchanged, the flux through these pathways may in part explain these findings. The identification of lipid species containing 18:0 and 18:1 side chains being regulated alongside changes to glucose production may indicate potential mediators of glucose production and insulin resistance. Three-condition experiment, Vehicle, Palmitate (PA) and Palmitate (PA) + Metformin (Met) + Sodium Sailcylate (NaS) with biological replicates: 8 Vehicle, 20 PA and 20 PA+Met+NaS , independently grown and harvested. One replicate per array.
2013-11-08 | E-GEOD-52204 | biostudies-arrayexpress