IGFBP-2 as a biomarker in NAFLD improves hepatic steatosis: an integrated bioinformatics and experimental study

Abstract

Background and aims: Non-alcoholic fatty liver disease (NAFLD) has become a common chronic liver disease in the world. Simple steatosis is the early phase of NAFLD. However, the molecular mechanisms underlying the development of steatosis have not yet been fully elucidated. Methods: Two public datasets (GSE48452 and GSE89632) through the Gene Expression Omnibus (GEO) database were used to identify differentially expressed genes (DEGs) in the development of steatosis. A total of 72 participants including 38 normal histological controls and 34 simple steatosis patients were included in this study. GO, KEGG and PPI network analysis were performed to explore the function of DEGs. The results were further confirmed in high-fat diet (HFD)-fed mice and oleate-treated HepG2 cells. Results: Total 57 DEGs including 31 up- and 26 down-regulated genes between simple steatosis patients and healthy controls were determined. GO and KEGG analysis showed that most of DEGs were enriched in the ligand-receptor signaling pathways. PPI network construction was used to identify the hub genes of the DEGs. MYC, ANXA2, GDF15, AGTR1, NAMPT, LEPR, IGFBP-2, IL1RN, MMP7 and APLNR were identified as hub genes. And IGFBP-2 expression was found to be reversely associated with hepatic steatosis, fasting insulin, HOMA-IR index and ALT levels. In HFD-fed mice, hepatic IGFBP-2 was also downregulated and negatively associated with hepatic triglyceride levels. Moreover, overexpression IGFBP-2 ameliorated the oleate induced accumulation of triglycerides in hepatocytes. Conclusions: This study identified novel gene signatures in the hepatic steatosis and will provide new understanding and molecular clues of hepatic steatosis.

Transcriptomic Analysis Reveals the Protective Effects of Empagliflozin on Lipid Metabolism in Nonalcoholic Fatty Liver Disease

“…These results suggested that the HFD treatment primarily affected lipid synthesis and metabolism. Our results are consistent with previous studies which also revealed lipid biosynthetic and lipid metabolic process were enriched in the biological process (Chen et al, 2021;Xu et al, 2021). These results indicate a large proportion of dysregulated protein-coding genes in the transcriptome of a NAFLD liver, associated with glycolipid metabolism.…”

Identification of Hub Genes Associated With Non-alcoholic Steatohepatitis Using Integrated Bioinformatics Analysis

“…What’s more, hepatic IGFBP2 expression correlates with its circulating level and is associated with hepatic metabolism and lipogenesis. Xu et al reported that overexpression of IGFBP2 blunted the accumulation of triglycerides in HepG2 cells ( Chen et al, 2021 ). Pia et al showed that IGFBP2 attenuated lipogenesis stimulated by IGF1 in hepatocytes ( Fahlbusch et al, 2020 ).…”

FGF1 ameliorates obesity‐associated hepatic steatosis by reversing IGFBP2 hypermethylation

“…Insulin‐like growth factor binding protein 2 (IGFBP2) has been identified as a key regulator of metabolic disorders, including obesity, MAFLD, and IR 28,29 . IGFBP2 expression has been found to be significantly diminished in visceral white adipose tissue and liver in obese mice 30 . Studies have demonstrated that low plasma levels of IGFBP2 are associated with IR that may develop into diabetes, 31,32 and its overexpression plays a protective role against the development of MAFLD and IR in obese mice.…”

“…28,29 IGFBP2 expression has been found to be significantly diminished in visceral white adipose tissue and liver in obese mice. 30 Studies have demonstrated that low plasma levels of IGFBP2 are associated with IR that may develop into diabetes, 31,32 and its overexpression plays a protective role against the development of MAFLD and IR in obese mice. Mechanistically, IGFBP2 has been shown to activate Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway causing intracellular translocation of glucose transporter type 4 (GLUT4) and stimulation of glucose uptake.…”