Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 26:15:1338889.
doi: 10.3389/fendo.2024.1338889. eCollection 2024.

Key genes involved in nonalcoholic steatohepatitis improvement after bariatric surgery

Xiyu Chen  1 , Shi-Zhou Deng  1 , Yuze Sun  1 , Yunhu Bai  1   2 , Yayun Wang  3 , Yanling Yang  1
Affiliations

Key genes involved in nonalcoholic steatohepatitis improvement after bariatric surgery

Xiyu Chen et al. Front Endocrinol (Lausanne). .

Abstract

Background: Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver diseases. The effectiveness of bariatric surgery in treating NASH and preventing or even reversing liver fibrosis has been demonstrated in numerous clinical studies, but the underlying mechanisms and crucial variables remain unknown.

Methods: Using the GSE135251 dataset, we examined the gene expression levels of NASH and healthy livers. Then, the differentially expressed genes (DEGs) of patients with NASH, at baseline and one year after bariatric surgery, were identified in GSE83452. We overlapped the hub genes performed by protein-protein interaction (PPI) networks and DEGs with different expression trends in both datasets to obtain key genes. Genomic enrichment analysis (GSEA) and genomic variation analysis (GSVA) were performed to search for signaling pathways of key genes. Meanwhile, key molecules that regulate the key genes are found through the construction of the ceRNA network. NASH mice were induced by a high-fat diet (HFD) and underwent sleeve gastrectomy (SG). We then cross-linked the DEGs in clinical and animal samples using quantitative polymerase chain reaction (qPCR) and validated the key genes.

Results: Seven key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF1) with different expression trends in GSE135251 and GSE83452 were obtained with the top 30 hub genes selected by PPI. The expression of seven key genes in mice after SG was validated by qPCR. Combined with the qPCR results from NASH mice, the four genes FASN, SCD, HMGCS1, and CXCL10 are consistent with the biological analysis. The GSEA results showed that the 'cholesterol homeostasis' pathway was enriched in the FASN, SCD, HMGCS1, and SQLE high-expression groups. The high-expression groups of CD68 and CXCL10 were extremely enriched in inflammation-related pathways. The construction of the ceRNA network obtained microRNAs and ceRNAs that can regulate seven key genes expression.

Conclusion: In summary, this study contributes to our understanding of the mechanisms by which bariatric surgery improves NASH, and to the development of potential biomarkers for the treatment of NASH.

Keywords: bariatric surgery; competitive endogenous RNA; gene expression omnibus datasets; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; sleeve gastrectomy.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The work flowchart in this study.
Figure 2
Figure 2
Identification and Enrichment analysis of DEGs in GSE135251 and GSE83452. (A) Volcano plots of gene expression in GSE135251, with the threshold of P<0.05 and |log FC| > 0.5. (B) GO enrichment analysis of the DEGs in GSE135251. (C) KEGG enrichment analysis of the DEGs in GSE135251. (D) Volcano plots of gene expression in GSE83452. (E) GO enrichment analysis of the DEGs in GSE83452. (F) KEGG enrichment analysis of the DEGs in GSE83452. (E) Venn diagram of the common DEGs in GSE135251 and GSE83452. (F) GO enrichment analysis of the common DEGs. (G) KEGG enrichment analysis of the common DEGs.
Figure 3
Figure 3
PPI network of common genes and identification of key genes. (A–C) PPI nrtwork of 75 common DEGs in GSE135251 and GSE83452. (D) Venn diagram of candidate DEGS down-regulation in GSE135251 and up-regulation in GSE83452. (E) Venn diagram of candidate genes up-regulation in GSE135251 and down-regulation in GSE83452. (F) Venn diagram of top 30 DEGs of PPI and 23 candidate genes in (D, E), obtained 7 key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF-1). (G) 7 key genes expression in NASH dataset GSE48452. (H) 7 key genes expression in NASH dataset GSE61260. (I) Merge the expression of 7 key genes in two datasets (G, H).
Figure 4
Figure 4
Gene set enrichment analysis (GSEA) of key genes in HALLMARK gene set. GSEA of FASN (A), SCD (B), CD68 (C), HMGCS1 (D), SQLE (E), CXCL10 (F), and IGF1 (G) in HALLMARK gene set.
Figure 5
Figure 5
Gene set variation analysis (GSVA) of key genes in HALLMARK gene set. GSVA of FASN (A), SCD (B), CD68 (C), HMGCS1 (D), SQLE (E), CXCL10 (F), and IGF1 (G) in HALLMARK gene set.
Figure 6
Figure 6
ceRNA network construction of key genes. ceRNA network construction of FASN (A), SCD (B), CD68 (C), HMGCS1 (D), SQLE (E), CXCL10 (F), and IGF1 (G).
Figure 7
Figure 7
Role of seven key genes in remission of NASH after bariatric surgery. Fatty acid synthase (FASN) is a key enzyme in fatty acid synthesis. Malonyl-CoA is changed into fatty acids (FA) by FASN. Steroidal coenzyme A desaturase (SCD) is the rate-limiting enzyme of monounsaturated fatty acids and a key enzyme in the synthesis of triglycerides (TG). It has been observed that lowering SCD enhances insulin sensitivity. Hydroxy-3-methylglutaryl-CoA synthetase 1 (HMGCS1) is a protein-coding gene associated with cholesterol (TC) biosynthesis and steroid metabolism and promotes FA synthesis and disruption of lipid metabolism. The enzyme squalene epoxidase (SQLE) limits the rate at which TC is synthesized and encourages the build-up of TC and cholesteryl esters in hepatocytes. C-X-C motif chemokine 10 (CXCL10) is secreted by macrophages and causes an inflammatory cascade response when it interacts with its cognate receptor C-X-C motif receptor 3 (CXCR3), resulting in inflammation and hepatocyte damage. the expression of hepatic inflammation-related marker CD68 was elevated in NASH. Insulin-like growth factor 1 (IGF1) is primarily produced by growth hormone (GH) stimulated hepatic production in adults. IGF1-induced insulin sensitization has been in rodent models of liver disease, including models of NAFLD and NASH. And IGF1 can have an anti-inflammatory effect by acting on macrophages. Bariatric surgery alleviates NASH by altering the expression of these seven key genes, reducing liver steatosis, hepatocyte damage, inflammation.
Figure 8
Figure 8
Establishment of mouse NASH model and key gene expression. (A) Flow chart of HFD-NASH mice (n=6/group). (B) Gross morphology, H&E staining and Oil Red O staining of hepatic tissue from control and HFD diet mice (16 weeks on the indicated diet, n=6/group), Scale bar: 200mm. (C) Percentage of liver tissue with steatosis. (D) Intraperitoneal glucose tolerance test (IPGTT) and the areas under the curve (AUC) at 16 weeks after the indicated diet (n=6/group). (E) Serum free fatty acid (FFA) content at 16 weeks after indicated diet (n=6/group). (F) Intraperitoneal insulin tolerance test (IPITT) and AUC at 16 weeks after indicated diet (n=6/group). (G) Relative mRNA expression in the liver of 7 key genes by qPCR (16 weeks after indicated diet, n=6/group). All Figures: ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 9
Figure 9
The expression of 7 key genes after SG. (A) Flow chart of SG (n=6/group). (B) HE staining and Oil Red O staining of liver tissue from sham and SG group (8 weeks post-surgery, n=6/group), Scale bar: 200mm. (C) Percentage of liver tissue with steatosis. (D) The main procedure of SG; a: Expose the body of stomach; b: Fix the gastric body with ophthalmic forceps; c: Excise the greater curvature of stomach; d: Suture stump. (E) IPGTT and AUC at 8 weeks post-surgery (n=6/group). (F) Serum FFA content at 8 weeks post-surgery (n=6/group). (G) IPITT and AUC at 8 weeks post-surgery (n=6/group). (H) Relative mRNA expression in the liver of 7 key genes by qPCR at 8 weeks post-surgery (n=6/group).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. . Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol (2018) 15(1):11–20. doi: 10.1038/nrgastro.2017.109 - DOI - PubMed
    1. Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, et al. . Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatol (Baltimore Md) (2019) 69(6):2672–82. doi: 10.1002/hep.30251 - DOI - PubMed
    1. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. . The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterol (2005) 129(1):113–21. doi: 10.1053/j.gastro.2005.04.014 - DOI - PubMed
    1. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: A review. JAMA (2020) 323(12):1175–83. doi: 10.1001/jama.2020.2298 - DOI - PubMed
    1. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. . The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatol (Baltimore Md) (2018) 67(1):328–57. doi: 10.1002/hep.29367 - DOI - PubMed