Lipid Synthesis Is Required to Resolve Endoplasmic Reticulum Stress and Limit Fibrotic Responses in the Lung

Abstract

Endoplasmic reticulum (ER) stress is evident in the alveolar epithelium of humans and mice with pulmonary fibrosis, but neither the mechanisms causing ER stress nor the contribution of ER stress to fibrosis is understood. A well-recognized adaptive response to ER stress is that affected cells induce lipid synthesis; however, we recently reported that lipid synthesis was downregulated in the alveolar epithelium in pulmonary fibrosis. In the present study, we sought to determine whether lipid synthesis is needed to resolve ER stress and limit fibrotic remodeling in the lung. Pharmacologic and genetic manipulations were performed to assess whether lipid production is required for resolving ER stress and limiting fibrotic responses in cultured alveolar epithelial cells and whole-lung tissues. Concentrations of ER stress markers and lipid synthesis enzymes were also measured in control and idiopathic pulmonary fibrosis lung tissues. We found that chemical agents that induce ER stress (tunicamycin or thapsigargin) enhanced lipid production in cultured alveolar epithelial cells and in the mouse lung. Moreover, lipid production was found to be dependent on the enzyme stearoyl-coenzyme A desaturase 1, and when pharmacologically inhibited, ER stress persisted and lung fibrosis ensued. Conversely, lipid production was reduced in mouse and human fibrotic lung, despite there being an increase in the magnitude of ER stress. Furthermore, augmenting lipid production effectively reduced ER stress and mitigated fibrotic remodeling in the mouse lung after exposure to silica. Augmenting lipid production reduces ER stress and attenuates fibrotic remodeling in the mouse lung, suggesting that similar approaches might be effective for treating human fibrotic lung diseases.

Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

“…Mice with Apoe deletion showed impaired alveologenesis, low lung function, and shorter life span compared to wild type mice (Massaro and Massaro, 2008). Lipid synthesis is required to resolve endoplasmic reticulum stress and limit fibrotic responses in the lung (Romero et al, 2018). Targeted deletion FASN (fatty acid synthase) in AEC2s worsened bleomycin-induced lung fibrosis (Chung et al, 2019).…”

A metabolic handbook for the COVID-19 pandemic

“…In fibrotic lungs, epithelial cells accumulate large aggregates of misfolded proteins, which cause endoplasmic reticulum stress. Similarly, inhibition of stearoyl-CoA desaturase, an enzyme involved in the desaturation of fatty acids, causes endoplasmic reticulum stress and pulmonary fibrosis in mice 96 , thus suggesting that epithelial cell metabolism may control the endoplasmic reticulum stress in fibrotic lungs. Chu et al have reported that fibrotic patients have higher palmitate levels in their lungs than control individuals.…”

Alveolar lipids in pulmonary disease. A review

“…For example, enhanced autophagy in Golgin A2 (GOLGA2) −/− mice limited the subcellular availability of functional mitochondria and lamellar bodies, and this was associated with decreased DPPC and a mild increase in extracellular matrix (ECM) deposition in both lungs and liver [147]. Intranasal tunicamycin increased ER stress, as well as expression of lipogenic enzymes fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1) and diglyceride acyltransferase (DGAT), their upstream regulator SREBP1, and intracellular triglyceride and PL content [148]. Loss of mitochondrial mitofusin 1 or 2, as well as inhibition of FAS in T2C, worsened bleomycin-induced fibrosis and was associated with perturbed surfactant lipid metabolism [149].…”

“…The sole inhibition of SCD1 was enough to induce ER stress and collagen deposition. It was not determined if the potentially increased proportion of saturated fatty acids, including palmitic, resulting of SCD1 inhibition could contribute to this ER stress [148,151]. Lipid metabolic pathways are often challenging to interpret unless direct metabolite measurements are performed, since same fatty acid substrates can result in different products, with different implications in metabolic and inflammatory pathways, highlighting the relevance and complexity of metabolic fluxes in different cellular conditions.…”