Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice - PubMed (original) (raw)
Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice
Flavia Maria Silva-Veiga et al. World J Gastroenterol. 2022.
Abstract
Background: Obesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation.
Aim: To address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice.
Methods: Male C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin).
Results: The HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation.
Conclusion: PPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.
Keywords: Dipeptidyl-peptidase-4-inhibitor; Dysbiosis; High-fat diet; Inflammation; Nonalcoholic fatty liver disease; Peroxisome proliferator-activated receptor-alpha.
©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Conflict of interest statement
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Figures
Figure 1
Body mass and food behavior. A: Body mass evolution; B: Food intake; C: Energy intake. Brown-Forsythe and Welch one-way ANOVA and Dunnett T3 post hoc test (mean ± SD, n = 6). Significant differences are indicated as follows: a_P_ < 0.05; b_P_ < 0.01; d_P_ < 0.0001. C: Control diet; HF: High-fat diet; HFA: High-fat diet plus PPAR-alpha agonist (WY14643); HFL: High-fat diet plus DPP-4 inhibitor (linagliptin); HFC: High-fat diet plus the combination of WY14643 with linagliptin.
Figure 2
Carbohydrate metabolism. A: Oral glucose tolerance test; B: Area under the curve for oral glucose tolerance test; C: Plasma glucagon-like peptide 1 concentrations. Brown-Forsythe and Welch one-way ANOVA and Dunnett T3 post hoc test (mean ± SD, n = 6). Significant differences are indicated as follows: a_P_ < 0.05; c_P_ < 0.001; d_P_ < 0.0001. C: Control diet; HF: High-fat diet; HFA: High-fat diet plus PPAR-alpha agonist (WY14643); HFL: High-fat diet plus DPP-4 inhibitor (linagliptin); HFC: High-fat diet plus the combination of WY14643 with linagliptin; AUC: Area under the curve; OGTT: Oral glucose tolerance test; GLP1: Glucagon-like peptide 1.
Figure 3
Gut-liver axis. A: Phylogenetic microbiota composition; B: Plasma lipopolysaccharide concentrations; C: Hepatic Lbp gene expression; D: Hepatic Tlr4 gene expression. Brown-Forsythe and Welch one-way ANOVA and Dunnett T3 post hoc test (mean ± SD, n = 6). Significant differences are indicated as follows: a_P_ < 0.05; b_P_ < 0.01; c_P_ < 0.001; d_P_ < 0.0001. C: Control diet; HF: High-fat diet; HFA: High-fat diet plus PPAR-alpha agonist (WY14643); HFL: High-fat diet plus DPP-4 inhibitor (linagliptin); HFC: High-fat diet plus the combination of WY14643 with linagliptin; LPS: Lipopolysaccharide.
Figure 4
Gut gene expression, histology, and stereology. A: Gut Mucin2; B: Zo-1; C: Occludin gene expression; D: Large intestine stained with Alcian Blue and Periodic Acid-Schiff (PAS); E: Numerical density of goblet cells per area. Alcian blue and PAS stain glycoproteins produced by goblet cells (scale bar = 40 μm), which were markedly reduced by the high-fat diet and rescued by the treatments according to stereology (QA goblet). Brown-Forsythe and Welch one-way ANOVA and Dunnett T3 post hoc test (mean ± SD, n = 6 for real-time reverse transcriptase–polymerase chain reaction and n = 5 for stereology). Significant differences are indicated as follows: a_P_ < 0.05; b_P_ < 0.01; c_P_ < 0.001; d_P_ < 0.0001. C: Control diet; HF: High-fat diet; HFA: High-fat diet plus PPAR-alpha agonist (WY14643); HFL: High-fat diet plus DPP-4 inhibitor (linagliptin); HFC: High-fat diet plus the combination of WY14643 with linagliptin; PAS: Periodic Acid-Schiff; QA: Numerical density per area.
Figure 5
Liver histology, stereology, and biochemistry. A: Hematoxylin-eosin liver sections; B: Volume density (Vv) (liver steatosis); C: Hepatic triacylglycerol. Liver sections show widespread hepatic steatosis after chronic HF diet intake and expressive reduction in all treated groups (scale bar = 50 μm. Both stereology (Vv steatosis) and biochemical analyses (hepatic triacylglycerol) confirm these observations. Brown-Forsythe and Welch one-way ANOVA and Dunnett T3 post hoc test (mean ± SD, n = 6 for biochemistry and n = 5 for stereology). Significant differences are indicated as follows: a_P_ < 0.05; b_P_ < 0.01; c_P_ < 0.001; d_P_ < 0.0001. C: Control diet; HF: High-fat diet; HFA: High-fat diet plus PPAR-alpha agonist (WY14643); HFL: High-fat diet plus DPP-4 inhibitor (linagliptin); HFC: High-fat diet plus the combination of WY14643 with linagliptin; Vv: Volume density.
Figure 6
Liver gene expression. A: Cd206; B: IL-10; C: Nlrp3; D: IL-13. Brown-Forsythe and Welch one-way ANOVA and Dunnett T3 post hoc test (mean ± SD, n = 5 or 6). Significant differences are indicated as follows: a_P_ < 0.05; b_P_ < 0.01; c_P_ < 0.001; d_P_ < 0.0001. C: Control diet; HF: High-fat diet; HFA: High-fat diet plus PPAR-alpha agonist (WY14643); HFL: High-fat diet plus DPP-4 inhibitor (linagliptin); HFC: High-fat diet plus the combination of WY14643 with linagliptin.
Figure 7
Main findings of the study. All treatments alleviated fatty liver by countering gut dysbiosis and rescuing the intestinal barrier integrity. The reduced lipopolysaccharide (LPS) influx to the liver caused reduced inflammasome and CD206 macrophage activation. Peroxisome proliferator-activated receptor-alpha activation and DPP-4 inhibition can be regarded as viable tools to treat leaky gut and prevent LPS-driven hepatic steatosis. PPAR: Peroxisome proliferator-activated receptor; DPP-4: Dipeptidyl peptidase-4; LPS: Lipopolysaccharide; LBP: Lipopolysaccharide-binding protein; TLR4: Toll-Like receptor 4; ZO-1: Zonula occludens 1; NLRP3: NLR family pyrin domain containing 3; CD206: Cluster of differentiation 206; IL: Interleukin. Created with Biorender:
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