Intestinal Depletion of TM6SF2 Exacerbates High-fat Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease through the Gut-liver Axis

Li-Zhen Chen; Yu-Rong Wang; Zhen-Zhen Zhao; Shou-Lin Zhao; Cong-Cong Min; Yong-Ning Xin

doi:10.14218/JCTH.2024.00407

Intestinal Depletion of TM6SF2 Exacerbates High-fat Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease through the Gut-liver Axis

J Clin Transl Hepatol. 2025 Jun 28;13(6):443-455. doi: 10.14218/JCTH.2024.00407. Epub 2025 Mar 12.

Authors

Li-Zhen Chen¹, Yu-Rong Wang², Zhen-Zhen Zhao³, Shou-Lin Zhao¹, Cong-Cong Min⁴, Yong-Ning Xin⁵

Affiliations

¹ Department of Infectious Disease, Qingdao Municipal Hospital,Qingdao University, Qingdao, Shandong, China.
² Department of Infectious Disease, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, Shandong, China.
³ Clinical Research Center, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China.
⁴ Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
⁵ Department of Infectious Disease, Qingdao Municipal Hospital,University of Health and Rehabilitation Sciences, Qingdao, Shandong, China.

Abstract

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common form of chronic liver disease worldwide. This study aimed to explore the role of TM6SF2 in high-fat diet (HFD)-induced MASLD through the gut-liver axis.

Methods: The TM6SF2 gut-specific knockout (TM6SF2 GKO) mouse was constructed using CRISPR/Cas9 technology. TM6SF2 GKO and wild-type (CON) mice were fed either a HFD or a control diet for 16 weeks to induce MASLD. Blood, liver, and intestinal lipid content, as well as gut microbiota and serum metabolites, were then analyzed.

Results: TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice. The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice. The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase, alanineaminotransferase, and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice, while triglyceride levels were lower. Serum metabolite analysis revealed that HFD-fed TM6SF2 GKO mice had an increase in the expression of 17 metabolites (e.g., LPC [18:0/0-0]) and a decrease in 22 metabolites (e.g., benzene sulfate). The differential metabolites of LPC (18:0/0-0) may serve as HFD-fed TM6SF2 serum biomarkers, leading to MASLD exacerbation in GKO mice.

Conclusions: TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice. TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.

Keywords: Gut microbiota; Gut-liver axis; High-fat diet; Lipid metabolism; Metabolic dysfunction-associated steatotic liver disease; Transmembrane 6 superfamily member 2.