Abnormal n-6 fatty acid metabolism in cystic fibrosis is caused by activation of AMP-activated protein kinase

Umunakwe, Obi C.; Seegmiller, Adam C.

doi:10.1194/jlr.m050369

Cited by 18 publications

(17 citation statements)

References 60 publications

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“…Consistent with the above findings, our lipidomic analysis showed an increase in AA/LA and AA/DHA ratios in Cftr‐defective cells compared to their controls. Recent data showed that CFTR may alter AA/LA metabolism through an adenosine monophosphate–activated protein kinase–mediated increase in Δ5 and Δ6 desaturases . Altered AA/LA ratio and a lower production of DHA‐mediated endogenous activators of PPAR‐γ in CF biliary cells may account for the increased expression of the receptor as a compensatory mechanism to counteract a lower activation state.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium

et al. 2015

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Cystic fibrosis-associated liver disease (CFLD) is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up-regulation of TLR4/NF-kB-dependent immune mechanisms plays a major role in the pathogenesis of CFLD, and may represent a therapeutic target. Nuclear receptors (NRs) are transcription factors that regulate several intracellular functions. Some NRs, including peroxisome proliferator-activated receptor-γ (PPAR-γ), may counter-regulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in Cftr-KO mice exposed to DSS, and in vitro in primary cholangiocytes isolated from wild type and from Cftr-KO mice exposed to LPS. We found that in CFTR-defective biliary epithelium, expression of PPAR-γ is increased, but does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) upregulates PPAR-γ-dependent genes, while inhibiting the activation of NF-kB and the secretion of proinflammatory cytokines (LIX, MCP-1, MIP-2, G-CSF, KC) in response to LPS. PPAR-γ agonists modulate NF-kB-dependent inflammation by upregulating IkBα, a negative regulator of NF-kB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-KO mice exposed to a DSS-induced portal endotoxemia. Conclusion These studies unravel a novel function of PPAR-γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes.

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Section: Discussionmentioning

confidence: 99%

Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium

et al. 2015

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“…At least two studies using cultured respiratory epithelial cells have demonstrated increased activation of AMPK in CF compared with wild-type respiratory epithelial cells, as measured by increased phosphorylation of AMPKα and AMPK target acetyl CoA carboxylase (ACC) [ 59 , 60 ]. Furthermore, inhibition of AMPK activity normalized Δ5- and Δ6-desaturase expression and activity in CF cells to control cell levels [ 60 ]. Exogenous activation of AMPK had the opposite effect, increasing desaturase expression in wild-type cells to CF cell levels.…”

Section: Signalling Pathways Associated With Fatty Acid Abnormalitmentioning

confidence: 99%

“…However, while studies have shown no AMP excess in CF cells [ 59 ], there is clear evidence of alterations in Ca 2+ transport and metabolism, leading to increased Ca 2+ concentration in CF cells [ 63 , 64 ]. Accordingly, inhibition of CaMKKβ, either by a small molecule inhibitor or by Ca 2+ sequestration, resulted in normalization of desaturase expression and activity in CF cells [ 60 ]. These findings suggest that altered Ca 2+ metabolism and CaMKKβ activity are upstream of AMPK activation in CF.…”

Section: Signalling Pathways Associated With Fatty Acid Abnormalitmentioning

confidence: 99%

Abnormal Unsaturated Fatty Acid Metabolism in Cystic Fibrosis: Biochemical Mechanisms and Clinical Implications

Seegmiller

2014

IJMS

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Cystic fibrosis is an inherited multi-organ disorder caused by mutations in the CFTR gene. Patients with this disease exhibit characteristic abnormalities in the levels of unsaturated fatty acids in blood and tissue. Recent studies have uncovered an underlying biochemical mechanism for some of these changes, namely increased expression and activity of fatty acid desaturases. Among other effects, this drives metabolism of linoeate to arachidonate. Increased desaturase expression appears to be linked to cystic fibrosis mutations via stimulation of the AMP-activated protein kinase in the absence of functional CFTR protein. There is evidence that these abnormalities may contribute to disease pathophysiology by increasing production of eicosanoids, such as prostaglandins and leukotrienes, of which arachidonate is a key substrate. Understanding these underlying mechanisms provides key insights that could potentially impact the diagnosis, clinical monitoring, nutrition, and therapy of patients suffering from this deadly disease.

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“…This increase in Δ5and Δ6-desaturase activity could be due to a loss of proper CFTR function, which leads to an increase in intracellular calcium that activates calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), which activates 5' AMP-activated protein kinase (AMPK). Inhibiting CaMKKβ or AMPK returns Δ5and Δ6-desaturase to control levels 19 . The decreased levels of DHA are likely due to increased retroconversion of DHA to its precursor molecule 20 .…”

Section: Lipid Imbalances In Cf Epitheliamentioning

confidence: 99%

The bidirectional relationship between CFTR and lipids

2020

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Cystic Fibrosis (CF) is the most common life-shortening genetic disease among Caucasians, resulting from mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). While work to understand this protein has resulted in new treatment strategies, it is important to emphasize that CFTR exists within a complex lipid bilayera concept largely overlooked when performing structural and functional studies. In this review we discuss cellular lipid imbalances in CF, mechanisms by which lipids affect membrane protein activity, and the specific impact of detergents and lipids on CFTR function. C ystic Fibrosis (CF) affects more than 70,000 individuals worldwide. Currently, lung failure is the leading cause of death, although many patients suffer from pancreatic insufficiency, wherein digestive enzymes are not delivered from the pancreas to the gastrointestinal tract 1. In 1989, the gene and protein associated with CF were identified and named the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) 2,3. CFTR is a member of the ATP-Binding Cassette Transporter superfamily (ABCC7). However, whereas all other ABC transporters use ATP to power an enzymatic function, CFTR is the only ABC transporter that functions primarily as an ion channel. Specifically, CFTR conducts chloride and bicarbonate. CFTR's domain architecture includes two transmembrane domains (each with six transmembrane helices (TMs)), two nucleotide binding domains, and a regulatory R-region (Fig. 1). Opening of the CFTR channel requires phosphorylation of the R-region by protein kinase A (PKA) and binding and subsequent hydrolysis of ATP at the nucleotide binding domains 4. Interestingly, the entirety of CFTR is sensitive to mutation, with some 2000 genetic variants having been described. However, F508del-CFTR is by far the most common variant, with ã 70% allele frequency in U.S. patients (https://www.cftr2.org/). Even the ultimate effect of these mutations on CFTR is complex, which is why seven different classes of mutations have been described (Table 1) 5,6. For a subset of these mutations, small-molecule therapeutics exist that increase the activity of CFTR. The first FDA-approved drug, VX-770 (Ivacaftor, KALYDECO ®) 7 , is a gating potentiator that helps certain CFTR mutants conduct more chloride upon activation by sub-maximal phosphorylation 8. The second drug, VX-809 (Lumacaftor), is a trafficking corrector that helps certain CFTR mutants reach the cell membrane 9. Lumacaftor is only ever administered in

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Abnormal n-6 fatty acid metabolism in cystic fibrosis is caused by activation of AMP-activated protein kinase

Cited by 18 publications

References 60 publications

Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium

Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium

Abnormal Unsaturated Fatty Acid Metabolism in Cystic Fibrosis: Biochemical Mechanisms and Clinical Implications

The bidirectional relationship between CFTR and lipids

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