Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2022; 28(17): 1814-1829
Published online May 7, 2022. doi: 10.3748/wjg.v28.i17.1814
Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice
Flavia Maria Silva-Veiga, Carolline Santos Miranda, Isabela Macedo Lopes Vasques-Monteiro, Henrique Souza-Tavares, Fabiane Ferreira Martins, Julio Beltrame Daleprane, Vanessa Souza-Mello
Flavia Maria Silva-Veiga, Carolline Santos Miranda, Isabela Macedo Lopes Vasques-Monteiro, Henrique Souza-Tavares, Fabiane Ferreira Martins, Vanessa Souza-Mello, Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Rio de Janeiro 20551-030, Brazil
Julio Beltrame Daleprane, Department of Clinical and Toxicology Analysis, State University of Rio de Janeiro, Nutrition Institute, State University of Rio de Janeiro, Nutrition Institute, University of Sao Paulo, Rio de Janeiro 20551-030, Brazil
Author contributions: Silva-Veiga FM, Martins FF, Daleprane JB, and Souza-Mello V designed and coordinated the study; Silva-Veiga FM, Miranda CS, Vasques-Monteiro IML, Souza-Tavares H, Martins FF, Daleprane JB, and Souza-Mello V performed the experiments, acquired and analyzed data; Silva-Veiga FM, Miranda CS, Vasques-Monteiro IML, Martins FF, Daleprane JB, and Souza-Mello V interpreted the data; Silva-Veiga FM and Souza-Mello V wrote the manuscript; all authors approved the final version of the article.
Supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil, No. CAPES–Finance Code 001; Fundação Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro (FAPERJ) to Souza-Mello V, No. E-26/202.657/2018 and No. E-26/010.002136/2019; The corresponding author is supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), No. 303785/2020-9.
Institutional review board statement: The study was reviewed and approved by the CEUA of State University of Rio de Janeiro Institutional Review Board, No. 041/2018.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at souzamello.uerj@gmail.com.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Vanessa Souza-Mello, PhD, Associate Professor, Department of Anatomy, Institute of Biology, State University of Rio de Janeiro, Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Blvd. 28 de Setembro 87, Fundos, Vila Isabel, Rio de Janeiro 20551-030, Brazil. souzamello.uerj@gmail.com
Received: December 30, 2021
Peer-review started: December 30, 2021
First decision: January 27, 2022
Revised: February 4, 2022
Accepted: March 26, 2022
Article in press: March 26, 2022
Published online: May 7, 2022
Processing time: 119 Days and 13.8 Hours
ARTICLE HIGHLIGHTS
Research background

Gut microbiota can be modified by the dietary composition and play a role in fatty liver pathogenesis through endotoxemia. Peroxisome proliferator-activated receptor (PPAR)-alpha activation has previously rescued the gut–liver axis with anti-steatotic effects in high-fructose-fed mice, whereas a high-dose dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin) inhibited hepatic lipogenesis in high-fat-fed mice. The combination of these drugs could restore the gut–liver axis in obese mice.

Research motivation

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent among obese individuals and can evolve into harmful liver diseases. Currently, there is no treatment directly prescribed to counter NAFLD. Herein, we propose a drug combination (PPAR-alpha agonist plus DPP-4 inhibitor) that can alleviate fatty liver by modulating the gut–liver axis with anti-inflammatory properties.

Research objectives

To evaluate the effects of monotherapy with a PPAR-alpha agonist (WY14643) or a DPP-4 inhibitor (linagliptin) and their combined treatment on the gut–liver axis, highlighting the intestinal barrier, endotoxemia, and inflammatory pathways in the livers of high-fat-fed mice. These preclinical insights can help establish new strategies for the treatment of NAFLD.

Research methods

Mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HF, 50% of energy as lipids) for 12 wk. Then, the HF group was randomly divided into four groups: HF, HF-A (treated with the PPAR-alpha agonist), HFL (treated with the DPP-4 inhibitor), and HFC (treated with the combination of both drugs). The treatments lasted for five weeks. The gut–liver axis was assessed by histological, biochemical, stereological, and molecular techniques.

Research results

The HF diet yielded overweightness and oral glucose intolerance, altered gut microbiota composition, and decreased the numerical density of goblet cells and tight junction gene expression, with increased plasma lipopolysaccharide (LPS) concentrations and increased fatty liver. The combined treatment rescued all of these metabolic alterations by restoring the gut microbiota and intestinal barrier markers, resulting in decreased LPS concentrations and fatty liver through anti-inflammatory signals. Further studies may focus on the Proteobacteria phylum, whose alteration can trigger harmful signaling to the liver.

Research conclusions

The combination of PPAR-alpha activation with DPP-4 inhibition yielded marked anti-steatotic effects by modulating the gut–liver axis, with reduced endotoxemia and amelioration of the intestinal barrier histology and gene expression. In turn, the livers of obese mice treated with the drug combination benefited from downregulation of the Tlr4 and Nlrp3 pathways and exhibited a hepatic parenchyma similar to that in the C group. Of note, we used stereology to estimate the numerical density of goblet cells in cecum slides stained with Alcian Blue and Periodic Acid-Schiff. This technique can be used to assess the effects of different interventions on the intestinal barrier and leaky gut in further studies.

Research perspectives

This study brings novelty to the treatment of NAFLD, which is a challenge to the scientific community. Our results confirm the importance of the gut–liver axis in the pathogenesis of fatty liver and propose a combined treatment that targets the gut microbiota composition, endotoxemia, and intestinal barrier alterations to alleviate fatty liver through local anti-inflammatory effects in HF-fed mice.