Biology subjects

Schilke, R. M.

Publications and source records attributed to Schilke, R. M..

3 recordsLinked to original sources

bioRxiv2020

Macrophage-associated lipin-1 transcriptional co-regulatory activity is involved in atherosclerosis

During atherosclerosis, macrophages engulf and break down deposited modified low-density lipoproteins (modLDLs) into lipids and free fatty acids. The lipids and free fatty acids from these modLDLs either need to be stored during a process called glycerolipid synthesis or broken down during {beta}-oxidation. In addition, free fatty acids can activate transcription factors to promote a pro-resolving macrophage phenotype. The protein lipin-1 is involved in both glycerolipid synthesis and {beta}-oxidation. Lipin-1 enzymatic activity is a key step in the glycerolipid synthesis pathway; lipin-1 transcriptional co-regulatory activity either augments or represses various transcription factors that are activated via free fatty acids that promote {beta}-oxidation and inhibit inflammation. Lipin-1 enzymatic activity increases pro-inflammatory macrophage phenotypes and is atherogenic. In contrast, we have also demonstrated that lipin-1 transcriptional co-regulatory activity promotes pro-resolving macrophage phenotypes leading us to the hypothesis that lipin-1 transcriptional co-regulatory activity is atheroprotective. Using a mouse model to delete lipin-1 in myeloid cells, we have demonstrated that loss of lipin-1 increases plaque size and pro-inflammatory gene expression. We have also shown mice lacking lipin-1 in myeloid cells have increased plaque collagen deposition and larger necrotic core formation. Combined, these data suggest that though lipin-1 enzymatic activity is atherogenic, lipin-1 transcriptional co-regulatory activity is atheroprotective. Overall, the results suggest that the dual activities of lipin-1 contribute to atherosclerosis progression in opposite ways.

immunology↗

bioRxiv2020

Lipin-1 regulates lipid catabolism in pro-resolving macrophages.

Macrophages reprogram their metabolism to promote appropriate responses. Pro-resolving macrophages primarily utilize fatty acid oxidation as an energy source. Metabolites generated during the catabolism of fatty acids aid in the resolution of inflammation and tissue repair, but the regulatory mechanisms that control lipid metabolism in macrophages is not fully elucidated. In this current study we show that lipin-1, a phosphatidic acid phosphatase and regulator of lipid metabolism, is required for increased oxidative phosphorylation during IL-4 mediated responses. We also show that the transcriptional coregulatory function of lipin-1 is required for {beta}-oxidation in response to palmitate (free fatty acid) and apoptotic cell derived lipids. BMDMs lacking lipin-1 have a reduction in critical TCA cycle metabolites following IL-4 stimulation, suggesting a break in the TCA cycle that is supportive of lipid synthesis rather than lipid catabolism. Together, our data demonstrate that lipin-1 regulates intermediary metabolism within pro-resolving macrophages and highlights the importance of aligning macrophage metabolism with proper responses to stimuli.

immunology↗

bioRxiv2019

Lipin-1 contributes to IL-4 mediated macrophage polarization

Macrophage responses contribute to a diverse array of pathologies ranging from infectious disease to sterile inflammation. Polarization of macrophages determines their cellular function within biological processes. Lipin-1 is a phosphatidic acid phosphatase in which its enzymatic activity contributes to macrophage pro-inflammatory responses. Lipin-1 also possesses transcriptional co-regulator activity and whether this activity is required for macrophage polarization is unknown. Using mice that lack only lipin-1 enzymatic activity or both enzymatic and transcriptional coregulator activities from myeloid cells, we investigated the contribution of lipin-1 transcriptional co-regulator function towards macrophage wound healing polarization. Macrophages lacking both lipin-1 activities did elicit IL-4 mediated gene expression to levels seen in either wild-type or lipin-1 enzymatically deficient macrophages. Furthermore, we provide evidence that the lack of myeloid-associated lipin-1 transcriptional co-regulator activity leads to impaired full thickness excisional wound healing. Our study demonstrates that lipin-1 transcriptional co-regulatory activity contributes to macrophage polarization and the macrophage contribution to wound healing in vivo.

immunology↗