Efeitos da associação do PPAR-alfa e gama, isolados ou em associação, sobre o eixo intestino-fígado de camundongos alimentados com dieta hiperlipídica

Abstract

Excess saturated fat in the diet increases the plasma concentration of lipopolysaccharides (LPS), which compromise intestinal integrity by breaking down the structural proteins of tight junctions (TJs) and altering intestinal permeability. LPS leakage activates hepatic TLR4, which induces a series of inflammatory responses, contributing to the development of metabolic dysfunction-associated fatty liver disease (MAFLD). To date, there is no treatment exclusively aimed at MAFLD. Peroxisome proliferator-activated receptors (PPARs) are emerging as possible targets for treating this disease. The aim of this study is to analyze the effects of PPAR-α and PPAR-γ activation (alone or in combination) on the gut-liver axis, focusing on endotoxemia and hepatic inflammatory pathways related MAFLD in high-fat-fed mice. Male C57BL/6J were fed a control diet (C) or a high-fat diet (HF) for a 10-week treatment. After 10 weeks, the HF groups was subdivided to receive treatment for 4 weeks: HF, HF-α (WY14643), HF-γ (low-dose pioglitazone), and HF-αγ (combination). The obesogenic environment of the high-fat diet caused overweight, insulin resistance, gut dysbiosis, and impaired TJs gene expression, leading to endotoxemia and marked hepatic steatosis. All treatments reduced body mass, glucose intolerance, and insulin resistance. In particular, the HF-αγ group had a similar body mass to the C group. These metabolic benefits restored the gut microbiota diversity, increasing goblet cells per area, TJs and Mucin-2 gene expression in the intestine. Treatments also lowered the plasma LPS concentrations and hepatic steatotic genes, favoring beta-oxidation gene over lipogenesis, reduced macrophage infiltration in the liver, and hepatic steatosis mitigation. Treatment with PPAR agonists modulated the gut microbiota and the integrity of the intestinal barrier, alleviating hepatic steatosis. These results show that these agonists can contribute to metabolic-associated fatty liver disease treatment.