2310-PUB: Chronic Western Diets Initiate Fibrosis Progression in Nonalcoholic Fatty Liver of Male Mice Modifying the PPARγ Pathway via Mir-27b-5p Regulation

Increased fructose intake in Western diets contributes to metabolic diseases. However, the epigenetic mechanisms are mostly unknown. Here, six week-old C57BL/6J male and female mice were fed with a low-fat diet (LFD), high-fat diet (HFD), and high-fat high-fructose diet (HFD-HF) for 20 weeks. We determined that HFD-HF or HFD mice experienced significant metabolic dysregulation compared to the LFD. Metabolic changes in male mice were significantly dysregulated compared to female mice. HFD-HF and HDF male-specific responses included physiological/metabolic changes such as significant increased body weight, increased liver size, increased fasting glucose levels and downregulated PPARγ (P < 0.001), SCD1 (P < 0.05 to P < 0.01), and FAS (P < 0.05) protein expression. In contrast, female mice were less affected by HFD and HFD-HF. Interestingly, none of the groups exhibited less insulin sensitivity after 20 weeks of feeding when compared to LFD. As miR-27b contains a seed sequence in PPARγ, it was discovered that these changes are accompanied by male-specific upregulation of miR-27b-5p, which is even more pronounced in the HFD-HF group (P < 0.01 vs. LFD) compared to the HFD group (P < 0.05 vs. LFD). Other miR-27 subtypes were increased but not significantly. Fat ballooning in hepatocytes were increased in HFD fed mice compared to HFD-HF fed mice, however, the HFD-HF liver showed an increase in the number of small cells. Here, we concluded that our chronic western diet-composition administered for 20 weeks surpassed the nonalcoholic fatty liver (NAFL) stage and initiated liver fibrosis via miR-27b-5p-induced PPARγ downregulation.