Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1.

Chu-Sook Kim; Yoonhee Kwon; Suck-Young Choe; Sun-Myung Hong; Hoon Yoo; Tsuyoshi Goto; Teruo Kawada; Hye-Seon Choi; Yeonsoo Joe; Hun Taeg Chung; Rina Yu

Background: Obesity-induced hepatic lipid accumulation causes lipotoxicity, mitochondrial dysfunction, oxidative stress, and insulin resistance, and is implicated in non-alcoholic hepatic pathologies such as steatohepatitis and fibrosis. Heme oxygenase-1 (HO-1), an important antioxidant enzyme catalyzing the rate-limiting step in heme degradation, protects against oxidative stress, inflammation, and metabolic dysregulation. Here, we demonstrate that the phytochemical, quercetin, a natural polyphenol flavonoid, protects against hepatic steatosis in obese mice fed a high-fat diet, and that it does so by inducing HO-1 and stimulating increased hepatic mitochondrial oxidative metabolism. Methods: Male C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), and an HFD supplemented with quercetin for 9 weeks. Levels of mitochondrial biogenesis and oxidative metabolic transcripts/proteins were measured by real-time PCR and/or Western blotting. HO-1 transcripts/proteins were measured real-time PCR and/or Western blotting. Results: Quercetin upregulated genes involved in mitochondrial biogenesis and oxidative metabolism in lipid-laden hepatocytes and the livers of HFD-fed obese mice, and this was accompanied by increased levels of the transcription factor, nuclear erythroid 2-related factor 2 (Nrf-2), and HO-1 protein. The HO-1 inducer hemin and the HO-1 byproduct carbon monoxide (CO) also enhanced hepatic oxidative metabolism in HFD-fed obese mice. Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2. Conclusion: These findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway. Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

OBESITY complications; GLUCOSE intolerance; CONFIDENCE intervals; CELL culture; CARBON monoxide; OXYGENASES; ANIMAL experimentation; WESTERN immunoblotting; NON-alcoholic fatty liver disease; METABOLISM; QUERCETIN; MITOCHONDRIA; DESCRIPTIVE statistics; RESEARCH funding; DATA analysis software; ODDS ratio; POLYMERASE chain reaction; HISTOLOGY; INSULIN resistance; MICE; ENZYME inhibitors

Nutrition & Metabolism, 2015, Vol 12, Issue 1, p1

1743-7075

Academic Journal

10.1186/s12986-015-0030-5