Effects of apolipoprotein H downregulation on lipid metabolism, fatty liver disease, and gut microbiota dysbiosis

Yaming Liu; Yiqun Zhao; Qiusong Liu; Binbin Li; P Vineeth Daniel; Binbin Chen; Zeyi Wu

doi:10.1016/j.jlr.2023.100483

Effects of apolipoprotein H downregulation on lipid metabolism, fatty liver disease, and gut microbiota dysbiosis

J Lipid Res. 2024 Jan;65(1):100483. doi: 10.1016/j.jlr.2023.100483. Epub 2023 Dec 14.

Authors

Yaming Liu¹, Yiqun Zhao², Qiusong Liu³, Binbin Li⁴, P Vineeth Daniel⁴, Binbin Chen⁵, Zeyi Wu⁶

Affiliations

¹ Department of Gastroenterology and Hepatology, Xiamen University Zhongshan Hospital, Xiamen, FJ, China; Department of Digestive Diseases, School of Medicine, Xiamen University, Xiamen, FJ, China. Electronic address: yaming0856@gmail.com.
² Department of Gastroenterology and Hepatology, Xiamen University Zhongshan Hospital, Xiamen, FJ, China; Department of Digestive Diseases, School of Medicine, Xiamen University, Xiamen, FJ, China.
³ Department of Tumor and Vascular Interventional Radiology, Xiamen University Zhongshan Hospital, Xiamen, FJ, China.
⁴ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
⁵ Department of Digestive Diseases, School of Medicine, Xiamen University, Xiamen, FJ, China.
⁶ Department of Computer Science and Engineering, University of California, San Diego, CA, USA.

Abstract

Apolipoprotein H (APOH) downregulation can cause hepatic steatosis and gut microbiota dysbiosis. However, the mechanism by which APOH-regulated lipid metabolism contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) remains undetermined. Herein, we aim to explore the regulatory effect of APOH, mediated through various pathways, on metabolic homeostasis and MASLD pathogenesis. We analyzed serum marker levels, liver histopathology, and cholesterol metabolism-related gene expression in global ApoH^-/- C57BL/6 male mice. We used RNA sequencing and metabolomic techniques to investigate the association between liver metabolism and bacterial composition. Fifty-two differentially expressed genes were identified between ApoH^-/- and WT mice. The mRNA levels of de novo lipogenesis genes were highly upregulated in ApoH^-/- mice than in WT mice. Fatty acid, glycerophospholipid, sterol lipid, and triglyceride levels were elevated, while hyodeoxycholic acid levels were significantly reduced in the liver tissues of ApoH^-/- mice than in those of WT mice. Microbial beta diversity was lower in ApoH^-/- mice than in WT mice, and gut microbiota metabolic functions were activated in ApoH^-/- mice. Moreover, ApoH transcripts were downregulated in patients with MASLD, and APOH-related differential genes were enriched in lipid metabolism. Open-source transcript-level data from human metabolic dysfunction-associated steatohepatitis livers reinforced a significant association between metabolic dysfunction-associated steatohepatitis and APOH downregulation. In conclusion, our studies demonstrated that APOH downregulation aggravates fatty liver and induces gut microbiota dysbiosis by dysregulating bile acids. Our findings offer a novel perspective on APOH-mediated lipid metabolic dysbiosis and provide a valuable framework for deciphering the role of APOH in fatty liver disease.

Keywords: apolipoprotein H; bile acids and salts; cholesterol/metabolism; de novo lipogenesis; gut microbiota; hepatocyte; triglycerides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Down-Regulation
Dysbiosis / metabolism
Fatty Acids / metabolism
Gastrointestinal Microbiome*
Humans
Lipid Metabolism / genetics
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / metabolism
beta 2-Glycoprotein I / genetics
beta 2-Glycoprotein I / metabolism
beta 2-Glycoprotein I / pharmacology

Substances

beta 2-Glycoprotein I
Fatty Acids