Dataset Information

Global Analyses of Selective Insulin Resitance in Hepatocytes due to Palmitate Lipotoxicity

ABSTRACT: Obesity is tightly linked to hepatic steatosis and insulin resistance. One feature of this association is the paradox of selective insulin resistance: insulin fails to suppress hepatic gluconeogenesis but activates lipid synthesis in the liver. How lipid accumulation interferes selectively with some branches of hepatic insulin signaling is not well understood. Here we provide a resource, based on unbiased approaches and established in a simple cell culture system, to enable investigations of the phenomenon of selective insulin resistance. We analyzed the phosphoproteome of insulin-treated human hepatoma cells and identified sites in which palmitate selectively impairs insulin signaling. As an example, we show that palmitate interferes with insulin signaling to FoxO1, a key transcription factor regulating gluconeogenesis, and identify a possible mechanism. This model system, together with our comprehensive characterization of the proteome, phosphoproteome, and lipidome changes in response to palmitate treatment, provides a novel and useful resource for unraveling the mechanisms underlying selective insulin resistance.

OTHER RELATED OMICS DATASETS IN: MTBLS582

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

SUBMITTER: Zon Weng Lai

LAB HEAD: Tobias Walther

PROVIDER: PXD006395 | Pride | 2018-02-14

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2015_06_16_ZL_PA_20min_phosphoproteome_A1_150623073735.raw	Raw
	2015_06_16_ZL_PA_20min_phosphoproteome_A2_150623122743.raw	Raw
	2015_06_16_ZL_PA_20min_phosphoproteome_A2_150629031711.raw	Raw
	2015_06_16_ZL_PA_20min_phosphoproteome_A3_150623171853.raw	Raw
	2015_06_16_ZL_PA_20min_phosphoproteome_A3_150629080923.raw	Raw

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Publications

Global Analyses of Selective Insulin Resistance in Hepatocytes Caused by Palmitate Lipotoxicity.

Li Zhihuan Z Lai Zon Weng ZW Christiano Romain R Gazos-Lopes Felipe F Walther Tobias C TC Farese Robert V RV

Molecular & cellular proteomics : MCP 20180205 5

Obesity is tightly linked to hepatic steatosis and insulin resistance. One feature of this association is the paradox of selective insulin resistance: insulin fails to suppress hepatic gluconeogenesis but activates lipid synthesis in the liver. How lipid accumulation interferes selectively with some branches of hepatic insulin signaling is not well understood. Here we provide a resource, based on unbiased approaches and established in a simple cell culture system, to enable investigations of the ...[more]

PMID: 29414761

Similar Datasets

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.