Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity

Plantier, Laurent; Besnard, Valérie; Xu, Yan; Ikegami, Machiko; Wert, Susan E.; Hunt, Alan N.; Postle, Anthony D.; Whitsett, Jeffrey A.

doi:10.1074/jbc.m111.303669

Cited by 53 publications

(47 citation statements)

References 50 publications

(43 reference statements)

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“…This is based on our findings showing that several key factors (e.g., SREBF1, DGAT1) involved in TG synthesis are up-regulated in the alcohol-exposed lung (32). Most notably, we detected a marked increase in the transcription factor, Srebf1, in both whole lung and in cultured AEII cells.…”

Section: Discussionmentioning

confidence: 83%

“…Recent evidence indicates that Srebf1 plays an important role in regulating TG levels in the lung (33). Mice with deletions of insulin-induced gene 1 and insulin-induced gene 2, both of which encode for proteins that inhibit Srebf, displayed enhanced Srebf1 function associated with marked accumulation of TGs in both AEII cells and AMs (32,34,35). Conversely, deletion of the sterolregulatory-element-binding cleavageassociated protein, which is required for Srebf activation, was associated with a nonsignificant decrease in TG levels in AEII cells.…”

Section: Discussionmentioning

confidence: 92%

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Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Romero

Shah

Duong

et al. 2014

Am J Respir Cell Mol Biol

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Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and/or treating alcohol-related pulmonary disorders.Keywords: chronic alcohol ingestion; AMP-activated protein kinase; surfactant lipids; macrophage Clinical RelevanceChronic alcohol abuse is a risk factor for bacterial pneumonia and acute respiratory distress syndrome; the molecular mechanisms underlying this association are not understood. Our work demonstrates that chronic alcohol exposure induces significant metabolic changes in the lung, including marked accumulation of triglycerides and free fatty acids within distal airspaces and alveolar macrophages (AMs). Furthermore, we provide evidence linking these lipid abnormalities to phenotypic and functional impairments in AMs, suggesting that these metabolic disturbances may contribute to the pathogenesis of alcohol-related inflammatory lung diseases. Together, these observations have broad implications for studying the effects of alcohol on lung homeostasis and immunity, and may be relevant to the pathogenesis of other inflammatory pulmonary disorders.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 92%

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Romero

Shah

Duong

et al. 2014

Am J Respir Cell Mol Biol

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“…Recruitment of macrophages is a common feature of patients with interstitial lung disease (13,44) and in mouse models of surfactant deficiency caused by disruption of surfactant lipid or protein homeostasis. For example, chronic AT2 cell injury caused by inhibition of SREBP, a transcriptional regulator of lipid homeostasis in AT2 cells, was associated with inflammation, expression of ARG1, and recruitment of atypical macrophages (45). Whether the recruitment of M2 macrophages to sites of alveolar cell proliferation contributes to repair or injury in the context of ABCA3-mediated lung disease will require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Alveolar injury and regeneration following deletion of ABCA3

Rindler¹,

Stockman²,

Filuta³

et al. 2017

JCI Insight

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“…FOXF1 expression was determined by immunohistochemistry on n ϭ 7 normal human lung biopsies and n ϭ 13 IPF lung biopsies, as described elsewhere (33). A goat polyclonal anti-FOXF1 antibody (AF4798, R&D Systems, Minneapolis, MN) was used at a final concentration of 0.2 g/ml.…”

Section: Methodsmentioning

confidence: 99%

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

Melboucy‐Belkhir

Pradère

Tadbiri

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Aberrant expression of master phenotype regulators or alterations in their downstream pathways in lung fibroblasts may play a central role in idiopathic pulmonary fibrosis (IPF). Interrogating IPF fibroblast transcriptome datasets, we identified Forkhead Box F1 (FOXF1), a DNA-binding protein required for lung development, as a candidate actor in IPF. Thus we determined FOXF1 expression levels in fibroblasts cultured from normal or IPF lungs in vitro, and explored FOXF1 functions in these cells using transient and stable loss-of-function and gain-of-function models. FOXF1 mRNA and protein were expressed at higher levels in IPF fibroblasts compared with normal fibroblasts (mRNA: ϩ44%, protein: ϩ77%). Immunohistochemistry showed FOXF1 expression in nuclei of bronchial smooth muscle cells, endothelial cells, and lung fibroblasts including fibroblastic foci of IPF lungs. In normal lung fibroblasts, FOXF1 repressed cell growth and expression of collagen-1 (COL1) and actin-related protein 2/3 complex, subunit 2 (ARPC2). ARPC2 knockdown inhibited cell growth and COL1 expression, consistent with FOXF1 acting in part through ARPC2 repression. In IPF fibroblasts, COL1 and ARPC2 repression by FOXF1 was blunted, and FOXF1 did not repress growth. FOXF1 expression was induced by the antifibrotic mediator prostaglandin E 2 and repressed by the profibrotic cytokine transforming growth factor-␤1 in both normal and IPF lung fibroblasts. Ex vivo, FOXF1 knockdown conferred CCL-210 lung fibroblasts the ability to implant in uninjured mouse lungs. In conclusion, FOXF1 functions and regulation were consistent with participation in antifibrotic pathways. Alterations of pathways downstream of FOXF1 may participate to fibrogenesis in IPF fibroblasts.

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Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity

Cited by 53 publications

References 50 publications

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

Alveolar injury and regeneration following deletion of ABCA3

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

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