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

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 326; no. 6; pp. G697 - G711
• Main Authors: Li, Xuemei, Tang, Xiaoqin, Xiang, Yue, Zhao, Zhibo, Li, Yanping, Ding, Qiuying, Zhang, Linkun, Xu, Jingyuan, Zhao, Lei, Chen, Yao
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2024
• Subjects: Acetate-CoA Ligase - metabolism; Acetylation; Animals; Diabetes mellitus; Epigenetics; Fatty liver; Glycosylation; Hepatocytes; Histones; Histones - metabolism; Hyperglycemia; Inflammation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lipid metabolism; Lipid Metabolism - physiology; Lipids; Liver - metabolism; Liver - pathology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Phosphorylation; Proteins; Proteolysis; Steatosis; Sterol regulatory element-binding protein; Trypsin; acetyl-CoA synthetase 2; SCAP; NASH; histone acetylation; N-glycosylation modification
• ISSN: 0193-1857; 1522-1547; 1522-1547
• DOI: 10.1152/ajpgi.00273.2023

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. -glycosylation of SCAP has been suggested to modulate cancer development, but its role in nonalcoholic steatohepatitis (NASH) is poorly understood. In this study, the -glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and glycosylation sites mutated SCAP were constructed to investigate the 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 sugar water (WD + SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation accompanied with hyperglycemia. In vitro, the enhanced glycosylation by high glucose increased the protein stability of SCAP and hence increased its total protein levels, whereas the ablation of glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, SCAP glycosylation increased not only the SREBP-1-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 the nuclear abolished the effects of SCAP glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes. glycosylation of SCAP exacerbates inflammation and lipid accumulation in hepatocytes through ACSS2-mediated H3K27ac. Our data suggest that SCAP glycosylation plays a key role in regulating histone H3K27 acetylation and targeting SCAP glycosylation may be a new strategy for treating nonalcoholic steatohepatitis (NASH).