Very Low Density Lipoprotein Receptor (VLDLR) Expression Is a Determinant Factor in Adipose Tissue Inflammation and Adipocyte-Macrophage Interaction

Nguyen, Andrew; Huan, Tao; Metrione, Michael; Hajri, Tahar

doi:10.1074/jbc.m113.515320

Cited by 53 publications

(60 citation statements)

References 51 publications

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“…Interestingly, recent data reveal that VLDLR deficiency strongly decreases HFD-induced lipid accumulation, inflammation, and ER stress in adipose tissue, in conjunction with reduced macrophage infiltration [17]. Another important player in the interplay between IR and ER stress in adipose tissue is the thioredoxin interacting protein (TXNIP), a mediator of IR and regulator of adipogenesis that inhibits glucose uptake in fat and muscle [18].…”

Section: Box 1 Upr Signal Transductionmentioning

confidence: 99%

Targeting endoplasmic reticulum stress in insulin resistance

Salvadó

Palomer

Barroso

et al. 2015

Trends in Endocrinology & Metabolism

189

150

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Section: Box 1 Upr Signal Transductionmentioning

confidence: 99%

Targeting endoplasmic reticulum stress in insulin resistance

Salvadó

Palomer

Barroso

et al. 2015

Trends in Endocrinology & Metabolism

189

150

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“…Lipid metabolism in macrophages has been shown to play an important role in triggering inflammation and ER stress (5,6) and has led to the identification of critical proteins that regulate the obesity-metabolic disease axis. For example, genetic ablation of the fatty acid binding protein (FABP4, also known as aP2) in macrophages alone is sufficient to protect mice from development of atherosclerosis and dyslipidemia (7).…”

mentioning

confidence: 99%

Uncoupling Lipid Metabolism from Inflammation through Fatty Acid Binding Protein-Dependent Expression of UCP2

Hertzel

Steen

et al. 2015

Molecular and Cellular Biology

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cChronic inflammation in obese adipose tissue is linked to endoplasmic reticulum (ER) stress and systemic insulin resistance. Targeted deletion of the murine fatty acid binding protein (FABP4/aP2) uncouples obesity from inflammation although the mechanism underlying this finding has remained enigmatic. Here, we show that inhibition or deletion of FABP4/aP2 in macrophages results in increased intracellular free fatty acids (FFAs) and elevated expression of uncoupling protein 2 (UCP2) without concomitant increases in UCP1 or UCP3. Silencing of UCP2 mRNA in FABP4/aP2-deficient macrophages negated the protective effect of FABP loss and increased ER stress in response to palmitate or lipopolysaccharide (LPS). Pharmacologic inhibition of FABP4/aP2 with the FABP inhibitor HTS01037 also upregulated UCP2 and reduced expression of BiP, CHOP, and XBP-1s. Expression of native FABP4/aP2 (but not the non-fatty acid binding mutant R126Q) into FABP4/aP2 null cells reduced UCP2 expression, suggesting that the FABP-FFA equilibrium controls UCP2 expression. FABP4/aP2-deficient macrophages are resistant to LPS-induced mitochondrial dysfunction and exhibit decreased mitochondrial protein carbonylation and UCP2-dependent reduction in intracellular reactive oxygen species. These data demonstrate that FABP4/aP2 directly regulates intracellular FFA levels and indirectly controls macrophage inflammation and ER stress by regulating the expression of UCP2.O besity-linked metabolic disorders, including insulin resistance, fatty liver disease, and coronary arterial disease, share the common signature of chronic inflammation and endoplasmic reticulum (ER) stress (1, 2). Macrophage and T cell infiltration and activation in adipose tissue play a key role in affecting adipokine synthesis and secretion, thereby regulating systemic insulin resistance (3). Inflammatory cytokines increase oxidative stress and decrease the protein-folding efficiency of the ER, initiating a counterregulatory unfolded protein response (UPR) (4) involving pancreatic ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme 1 (IRE1). Such concomitant activation leads to the downstream activation of response pathways and the induction of inflammatory signaling networks via c-Jun N-terminal kinase (JNK) and/or NF-B (nuclear factor kappa B) (1).Lipid metabolism in macrophages has been shown to play an important role in triggering inflammation and ER stress (5, 6) and has led to the identification of critical proteins that regulate the obesity-metabolic disease axis. For example, genetic ablation of the fatty acid binding protein (FABP4, also known as aP2) in macrophages alone is sufficient to protect mice from development of atherosclerosis and dyslipidemia (7). FABP4/aP2 is a cytoplasmic fatty acid (FA) carrier protein that mediates intracellular fatty acid trafficking, and a number of hypotheses have been proposed to explain why the loss of FABP4/aP2 results in metabolic improvement (6). Moreover, small molecules that target FABP4/aP2 have ...

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“…An inhibitory crosstalk exists between AMPK and ERK1/2 and activation of ERK1/2 inhibits AMPK and promotes ER stress-induced insulin resistance in skeletal muscle cells [14, 29]. Hence, VLDL and apoCIII-induced ER stress might be a result of the reduction in AMPK activity.…”

Section: Discussionmentioning

confidence: 99%

“…ApoCIII levels were determined using a nephelometric commercial kit (Kamiya Biomedical Company, Seattle, WA, USA) adapted to COBAS c501 autoanalyser. Cells were treated with 300 μg/ml of filtered VLDL, based on triacylglycerol concentration, as previously described [14]. …”

Section: Methodsmentioning

confidence: 99%

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

et al. 2017

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Aim/hypothesis Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle. Methods Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII. Results C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and in-flammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1α levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor. Conclusions/interpretation These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2.

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Very Low Density Lipoprotein Receptor (VLDLR) Expression Is a Determinant Factor in Adipose Tissue Inflammation and Adipocyte-Macrophage Interaction

Cited by 53 publications

References 51 publications

Targeting endoplasmic reticulum stress in insulin resistance

Targeting endoplasmic reticulum stress in insulin resistance

Uncoupling Lipid Metabolism from Inflammation through Fatty Acid Binding Protein-Dependent Expression of UCP2

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

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