UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Abstract

Aim: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. Methods: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE / mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. Results: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor (LXR ) activation, which was confirmed by the observation that LXR siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. Conclusions: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXR -dependent pathway.

Ufm1 inhibits LPS-induced endothelial cell inflammatory responses through the NF-κB signaling pathway

“…Previously, both our group (28) and other studies (27,29) indicate that Ufm1 is involved in ER stress, which is a key process of macrophage differentiation and cholesterol deposition in the development of AS (30–32). Our follow-up study also showed that Ufm1 is markedly upregulated under AS conditions and Ufm1 suppresses foam cell formation via the LXRα-dependent pathway (33). …”

“…It has been reported that Ufm1 is expressed in many tissues and cell lines (19,27) and that upregulation of Ufm1 expression is linked with the activation of the ER stress response in AS and diabetes (27,28,33,35). Our previous studies also demonstrated that Ufm1 is involved in AS conditions (28,33).…”

“…The Ufm1 cDNA sequence was obtained from 293 cells (obtained from ATCC) by reverse transcription of 293 cell mRNA and PCR amplification as previously described (33). Then the Ufm1 sequence was amplified and cloned into the pcDNA3.1 vector, along with a Flag tag in its N-terminus.…”

“…Western blot analysis was performed as previously described (28,33). Briefly, the HUVECs were dissected, homogenized, and solubilized at 4°C in Cell lysis buffer (P0013; Beyotime, Shanghai, China) supplemented with 1 mM PMSF, 50 mM NaF, 1 mM Na 3 VO 4 and protease inhibitor.…”

Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture

“…By searching functions of some newly detected genes, it seems that they have associations with cholesterol. For example, previous experimental analyses showed the gene UFM1 increase the macrophage cholesterol efflux, which might due to the increased expression of ATP-binding cassette transporters A1 ( ABCA1 ) and G1 ( ABCG1 )51; ABCA1 gene was reported to be associate with total cholesterol in previous genome-wide association study (GWAS)5. Previous GWAS reported the 400 kb upstream variant of UMF1 to be associate with plasma lipoprotein levels52.…”