Hydroxytyrosol promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes

Abstract 

Hydroxytyrosol (HT) in extra-virgin olive oil is considered one of the most important polyphenolic compounds responsible for the health benefits of the Mediterranean diet for lowering incidence of cardiovascular disease, the most common and most serious complication of diabetes. We propose that HT may prevent these diseases by a stimulation of mitochondrial biogenesis that leads to enhancement of mitochondrial function and cellular defense systems. In the present study, we investigated effects of HT that stimulate mitochondrial biogenesis and promote mitochondrial function in 3T3-L1 adipocytes. HT over the concentration range of 0.1–10 μmol/L stimulated the promoter transcriptional activation and protein expression of peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PPARGC1α, the central factor for mitochondrial biogenesis) and its downstream targets; these included nuclear respiration factors 1 and 2 and mitochondrial transcription factor A, which leads to an increase in mitochondrial DNA (mtDNA) and in the number of mitochondria. Knockdown of Ppargc1α by siRNA blocked HT's stimulating effect on Complex I expression and mtDNA copy number. The HT treatment resulted in an enhancement of mitochondrial function, including an increase in activity and protein expression of Mitochondrial Complexes I, II, III and V; increased oxygen consumption; and a decrease in free fatty acid contents in the adipocytes. The mechanistic study of the PPARGC1α activation signaling pathway demonstrated that HT is an activator of 5′AMP-activated protein kinase and also up-regulates gene expression of PPARα, CPT-1 and PPARγ. These data suggest that HT is able to promote mitochondrial function by stimulating mitochondrial biogenesis.

Keywords: 5′AMP-activated protein kinase (AMPK), Fatty acid oxidation, Mitochondrial transcription factor A (Tfam), Mitochondrial DNA (mtDNA), Nuclear respiration factors 1 and 2 (Nrf1 and Nrf2), Peroxisome proliferator-activated receptor coactivator 1 alpha (PPARGC1α)