Dietary Geranylgeraniol and Statins May Act Synergistically to Mitigate Oxidative Stress in Obese Mice

OBJECTIVES: This study aimed to determine the individual and combined effects of dietary geranylgeraniol (GG) and statins on oxidative stress in high-fat diet (HFD)-fed animals. METHODS: Five-week-old male C57BL/6J mice were stratified by initial body weight into a 2 × 2 factorial design with four groups: HFD (60% kcal from fat), HFD + statin (120 mg/kg diet), HFD + GG (400 mg/kg diet), or HFD + GG + statin. Following 14 weeks of treatment, mice were sacrificed, and liver was collected for analysis. Protein expression of the pro-oxidant enzyme, NADPH oxidase (NOX) 4, and antioxidant enzymes, superoxide dismutase 2 (SOD2) and catalase, as well as the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were assessed by western blot. Results were analyzed by two-way ANOVA followed by Tukey-Kramer post-hoc test. RESULTS: We found GG supplementation (HFD + GG group) reduced expression of NOX4 in the liver of obese mice, compared with the HFD group (0.41 ± 0.07-fold, n = 6, vs. 1.00 ± 0.24-fold, n = 6, p = 0.02). The combined, but not individual, treatment with statin and GG (HFD + GG + statin group) significantly increased the expression of SOD2 (1.68 ± 0.36-fold, n = 5, vs. 1.00 ± 0.12-fold, n = 6, p = 0.0002) and catalase (2.30 ± 0.57-fold, n = 5, vs. 1.00 ± 0.14-fold, n = 6, P < 0.0001) compared to the HFD group. Interestingly, NRF2 expression was increased only by statin treatment, without GG supplementation (HFD + GG group), (1.00 ± 0.45-fold, n = 6, vs. 2.20 ± 0.86-fold, n = 6, p = 0.03) compared to HFD. CONCLUSIONS: Oral statins and dietary GG have the potential to mitigate oxidative stress individually or in a synergistic manner by attenuating NOX4 and increasing antioxidant enzymes such as SOD2 and catalase. FUNDING SOURCES: American River Nutrition, LLC, Hadley, MA.