Abstract
BackgroundObesity-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.MethodsMale 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.ResultsQuercetin 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.ConclusionThese 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.
Highlights
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
We demonstrate that quercetin reduces lipid accumulation in primary hepatocytes and the livers of obese mice fed a high-fat diet, and that this is associated with enhanced hepatic mitochondrial oxidative metabolism and Heme oxygenase-1 (HO-1) induction
We showed that quercetin enhances hepatic mitochondrial oxidative metabolism in lipid-laden hepatocytes and the livers of obese mice fed a high-fat diet, and for the first time demonstrated a causal relationship between the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2)/HO-1, mitochondrial biogenesis and hepatic lipid accumulation using hemin, ZnPP and Carbon monoxide (CO)
Summary
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. Heme oxygenase-1 (HO-1), an important antioxidant enzyme catalyzing the rate-limiting step in heme degradation, is one of factors protecting against oxidative stress, inflammation, and metabolic dysregulation [5, 6]. We and others have reported that HO-1 induction by hemin protects against obesity-induced metabolic dysregulation by reducing adipose inflammation [9], which causes mitochondrial dysfunction leading to loss of oxidative capacity and hepatic lipid accumulation [4, 10]. We hypothesized that dietary factors that promote HO-1 induction and/or Nrf-2 activation might help to maintain hepatic mitochondrial oxidative capacity in obese conditions
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