Regulation of Lin28a-miRNA let-7b-5p pathway in skeletal muscle cells by peroxisome proliferator-activated receptor delta.

Lin28a/miRNA let-7b-5p pathway has emerged as a key regulators of energy homeostasis in the skeletal muscle. However, the mechanism through which this pathway is regulated in the skeletal muscle has remained unclear. We have found that 8 wk of aerobic training (Tr) markedly decreased let-7b-5p expression in murine skeletal muscle, whereas high-fat diet (Hfd) increased its expression. Conversely, Lin28a expression, a well-known inhibitor of let-7b-5p, was induced by Tr and decreased by Hfd. Similarly, in human muscle biopsies, Tr increased LIN28 expression and decreased let-7b-5p expression. Bioinformatics analysis of LIN28a DNA sequence revealed that its enrichment in peroxisome proliferator-activated receptor delta (PPARδ) binding sites, which is a well-known metabolic regulator of exercise. Treatment of primary mouse skeletal muscle cells or C2C12 cells with PPARδ activators GW501516 and AICAR increased Lin28a expression. Lin28a and let-7b-5p expression was also regulated by PPARδ coregulators. While PPARγ coactivator-1α (PGC1α) increased Lin28a expression, corepressor NCoR1 decreased its expression. Furthermore, PGC1α markedly reduced the let-7b-5p expression. PGC1α-mediated induction of Lin28a expression was blocked by the PPARδ inhibitor GSK0660. In agreement, Lin28a expression was downregulated in PPARδ knocked-down cells leading to increased let-7b-5p expression. Finally, we show that modulation of the Lin28a-let-7b-5p pathway in muscle cells leads to changes in mitochondrial metabolism in PGC1α dependent fashion. In summary, we demonstrate that Lin28a-let-7b-5p is a direct target of PPARδ in the skeletal muscle, where it impacts mitochondrial respiration.

Bisphenol-A exposure worsens hepatic steatosis in ovariectomized mice fed on a high-fat diet: Role of endoplasmic reticulum stress and fibrogenic pathways.

AIMS: Bisphenol (BP)-A exposure can impair glucose and lipid metabolism. However, it is unclear whether this endocrine disruptor (ED) modulates these processes in postmenopause, a period with organic changes that increase the risk for metabolic diseases. Herein, we evaluated the effects of BPA exposure on adiposity, glucose homeostasis and hepatic steatosis in ovariectomized (OVX) mice fed on a high-fat diet (HFD). MAIN METHODS: Adult Swiss female mice were OVX and submitted to a normolipidic diet or HFD and drinking water without [control (OVX CTL) and OVX HFD groups, respectively] or with 1 µg/mL BPA (OVX CBPA and OVX HBPA groups, respectively), for 3 months. KEY FINDINGS: OVX HFD females displayed increased adiposity, glucose intolerance, insulin resistance and moderate hepatic steatosis. This effect was associated with a high hepatic expression of genes involved in lipogenesis (Srebf1 and Scd1), ß-oxidation (Cpt1a) and endoplasmic reticulum (ER) stress (Hspa5 and Hyou1). BPA did not alter adiposity or glucose homeostasis disruptions induced by HFD. However, this ED triggered severe steatosis, exacerbating hepatic fat and collagen depositions in OVX HBPA, in association with a reduction in Mttp mRNA, and up-regulation of genes involved in ß-oxidation (Acox1 and Acadvl), mitochondrial uncoupling (Ucp2), ER stress (Hyou1 and Atf6) and chronic liver injury (Tgfb1and Casp8). Furthermore, BPA caused mild steatosis in OVX CBPA females, increasing the hepatic total lipids and mRNAs for Srebf1, Scd1, Hspa5, Hyou1 and Atf6. SIGNIFICANCE: BPA aggravated hepatic steatosis in OVX mice. Especially when combined with a HFD, BPA caused NAFLD progression, which was partly mediated by chronic ER stress and the TGF-ß1 pathway.