bims-meprid 2024-04-14 papers

Issue of 2024‒04‒14
two papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

bioRxiv. 2024 Mar 31. pii: 2024.03.28.587096. [Epub ahead of print]

The metabolic cofactor Coenzyme A enhances alternative macrophage activation via MyD88-linked signaling.

Anthony E Jones, Amy Rios, Neira Ibrahimovic, Carolina Chavez, Nicholas A Bayley, Andréa B Ball, Wei Yuan Hsieh, Alessandro Sammarco, Amber R Bianchi, Angel A Cortez, Thomas G Graeber, Alexander Hoffmann, Steven J Bensinger, Ajit S Divakaruni.

Metabolites and metabolic co-factors can shape the innate immune response, though the pathways by which these molecules adjust inflammation remain incompletely understood. Here we show that the metabolic cofactor Coenzyme A (CoA) enhances IL-4 driven alternative macrophage activation [m(IL-4)] in vitro and in vivo . Unexpectedly, we found that perturbations in intracellular CoA metabolism did not influence m(IL-4) differentiation. Rather, we discovered that exogenous CoA provides a weak TLR4 signal which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies revealed MyD88-linked signals prime for IL-4 responsiveness, in part, by reshaping chromatin accessibility to enhance transcription of IL-4-linked genes. The results identify CoA as a host metabolic co-factor that influences macrophage function through an extrinsic TLR4-dependent mechanism, and suggests that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.

DOI: https://doi.org/10.1101/2024.03.28.587096

Am J Physiol Gastrointest Liver Physiol. 2024 Apr 09.

N-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation.

Xuemei Li, Xiaoqin Tang, Yue Xiang, Zhibo Zhao, Yanping Li, Qiuying Ding, Linkun Zhang, Jingyuan Xu, Lei Zhao, Yao Chen.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in NASH is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with western diet and sweet water (WD+SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation. In vitro, the enhanced N-glycosylation increased the protein stability of SCAP and hence increased its total protein levels, while the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, the presence of SCAP N-glycosylation increased not only the SREBP1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in cytoplasm abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.

Keywords: Acetyl-CoA synthetase 2; N-glycosylation modification; NASH; SCAP; histone acetylation

DOI: https://doi.org/10.1152/ajpgi.00273.2023