Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice

Schiffrin, M. J.; Winkler, Carine; Quignodon, Laure; Naldi, Aurélien; Trötzmüller, Martin; Köfeler, Harald; Henry, Hugues; Parini, Paolo; Desvergne, Béatrice; Gilardi, Federica

doi:10.3390/ijms22189969

Cited by 14 publications

(10 citation statements)

References 54 publications

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“…Although not statistically significant, it is worth mentioning that HFD-treated females of both genotypes had lower liver lipid content compared to their male counterparts ( Table 2 ). However, data from SD-fed mice show higher total liver fat content in females vs. males ( Table S3 ), reinforcing the notion that females are more protected from liver fat accumulation upon HFD exposure [ 49 , 57 , 58 ]. The explanation for this dimorphism may lie in the oestrogen receptor α and its opposite regulation of lipid metabolism in male and female livers under dietary stress [ 49 ].…”

Section: Discussionsupporting

confidence: 56%

Tff3 Deficiency Protects against Hepatic Fat Accumulation after Prolonged High-Fat Diet

Šešelja

Bazina

Vrecl

et al. 2022

Life

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Trefoil factor 3 (Tff3) protein is a small secretory protein expressed on various mucosal surfaces and is involved in proper mucosal function and recovery via various mechanisms, including immune response. However, Tff3 is also found in the bloodstream and in various other tissues, including the liver. Its complete attenuation was observed as the most prominent event in the early phase of diabetes in the polygenic Tally Ho mouse model of diabesity. Since then, its role in metabolic processes has emerged. To elucidate the complex role of Tff3, we used a new Tff3-deficient mouse model without additional metabolically relevant mutations (Tff3-/-/C57BL/6NCrl) and exposed it to a high-fat diet (HFD) for a prolonged period (8 months). The effect was observed in male and female mice compared to wild-type (WT) counter groups (n = 10 animals per group). We monitored the animals’ general metabolic parameters, liver morphology, ultrastructure and molecular genes in relevant lipid and inflammatory pathways. Tff3-deficient male mice had reduced body weight and better glucose utilization after 17 weeks of HFD, but longer HFD exposure (32 weeks) resulted in no such change. We found a strong reduction in lipid accumulation in male Tff3-/-/C57BL/6NCrl mice and a less prominent reduction in female mice. This was associated with downregulated peroxisome proliferator-activated receptor gamma (Pparγ) and upregulated interleukin-6 (Il-6) gene expression, although protein level difference did not reach statistical significance due to higher individual variations. Tff3-/-/C57Bl6N mice of both sex had reduced liver steatosis, without major fatty acid content perturbations. Our research shows that Tff3 protein is clearly involved in complex metabolic pathways. Tff3 deficiency in C57Bl6N genetic background caused reduced lipid accumulation in the liver; further research is needed to elucidate its precise role in metabolism-related events.

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Section: Discussionsupporting

confidence: 56%

Tff3 Deficiency Protects against Hepatic Fat Accumulation after Prolonged High-Fat Diet

Šešelja

Bazina

Vrecl

et al. 2022

Life

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“…PPARG is mainly responsible for lipid catabolism, and it is related to NAFLD, obesity, diabetes, arteriosclerosis, etc. [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Protective Effects and Mechanism of Huaji Jianpi Decoction against Nonalcoholic Fatty Liver Disease by Network Pharmacology and Experimental Validation

Xue

Wang

Xiang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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This paper was designed to predict the mechanisms of the active components of Huaji Jianpi Decoction (HJJPD) against nonalcoholic fatty liver disease (NAFLD) based on network pharmacology-combined animal experiments. The candidate compounds of HJJPD and its relative targets were obtained from TCMSP and PharmMapper web server, and the intersection genes for NAFLD were discerned using OMIM, GeneCards, and DisGeNET. Then, the target protein-protein interaction (PPI) and component-target-pathway networks were constructed. Moreover, gene function annotation (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to study the potential signaling pathways associated with HJJPD’s effect on NAFLD. Molecular docking simulation was preformed to validate the binding affinity between potential core components and key targets. Eventually, the candidate targets, the possible pathway, and the mechanism of HJJPD were predicted by the network pharmacology-based strategy, followed by experimental validation in the NAFLD mice model treated with HJJPD. A total of 55 candidate compounds and 36 corresponding genes were identified from HJJPD that are associated with activity against NAFLD, and then the network of them was constructed. Inflammatory response and lipid metabolism-related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effect of the active bioactive ingredients on NAFLD. Compared with the model group, the liver wet weight, liver/body ratio, the levels of total cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and high-density lipoprotein (HDL) in serum in the HJJPD low-dose (17.52 g/kg·d), medium-dose (35.04 g/kg·d), and high-dose (70.07 g/kg·d) groups significantly decreased ( P < 0.05 ). Light microscope observation shows that HJJPD could control the degree of lipid denaturation of the mouse liver tissue to a great extent. RT-qPCR results show that the mRNA expression levels of peroxisome proliferative activated receptor gamma (PPARG), tumor necrosis factor-α (TNF-α), antiserine/threonine protein kinase 1 (AKT1), and prostaglandin-endoperoxide synthase (PTGS2) in the liver tissues of the three HJJPD groups (17.52 g/kg·d, 35.04 g/kg·d, and 70.07 g/kg·d) were significantly lower than those in the model group ( P < 0.05 ). HJJPD can exert its effect by inhibiting hepatic steatosis and related mRNA expression and decreasing the levels of other liver-related indexes. This study suggested that HJJPD exerted its effect on NAFLD by modulating multitargets with multicompounds through multipathways. It also demonstrated that the network pharmacology-based approach might provide insights for understanding the interrelationship between complex diseases and interventions of HJJPD.

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“…The liver exhibits a high degree of sexual dimorphism under normal health conditions, with hundreds of genes that are differentially expressed between the two sexes [ 3 , 4 ], contributing to the physiology, homeostasis and metabolism of compounds [ 5 , 6 , 7 ]. These sex differences also interfere with liver function and the susceptibility, development and consequences of liver diseases, such as non-alcoholic fatty liver disease (NAFLD) or its most severe manifestation and the most common primary liver tumor, hepatocellular carcinoma (HCC) [ 8 , 9 , 10 , 11 ]. In fact, it has been described that in both NAFLD and HCC, there is clear evidence of sexual dimorphism in both rodents and humans, with a significantly higher incidence in males [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Gender Dimorphism in Hepatic Carcinogenesis-Related Gene Expression Associated with Obesity as a Low-Grade Chronic Inflammatory Disease

Izquierdo

Carreira

Rodríguez-Carnero

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) show clear evidence of sexual dimorphism, with a significantly higher incidence in males. Among the determining factors that could explain this sex-based difference, the specific distribution of fat by sex has been suggested as a primary candidate, since obesity is a relevant risk factor. In this context, obesity, considered a low-grade chronic inflammatory pathology and responsible for the promotion of liver disease, could lead to sexual dimorphism in the expression profile of genes related to tumor development. When we compared the expression levels of genes associated with the early stages of carcinogenesis in the liver between male and female diet-induced obesity (DIO) rats, we observed that the expression pattern was similar in obese male and female animals. Interestingly, the SURVIVIN/BIRC5 oncogene showed a higher expression in male DIO rats than in female DIO and lean rats. This trend related to sexual dimorphism was observed in leukocytes from patients with obesity, although the difference was not statistically significant. In conclusion, this study evidenced a similar pattern in the expression of most carcinogenesis-related genes in the liver, except SUVIVIN/BIRC5, which could be a predictive biomarker of liver carcinogenesis predisposition in male patients with obesity.

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Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice

Cited by 14 publications

References 54 publications

Tff3 Deficiency Protects against Hepatic Fat Accumulation after Prolonged High-Fat Diet

Tff3 Deficiency Protects against Hepatic Fat Accumulation after Prolonged High-Fat Diet

Exploring the Protective Effects and Mechanism of Huaji Jianpi Decoction against Nonalcoholic Fatty Liver Disease by Network Pharmacology and Experimental Validation

Gender Dimorphism in Hepatic Carcinogenesis-Related Gene Expression Associated with Obesity as a Low-Grade Chronic Inflammatory Disease

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