Abstract
Recent evidence demonstrated that chronic intake of quercetin attenuated hepatic fat accumulation in various animal models of obesity and diabetes. However, whether quercetin has the ability to enhance energy metabolism in hepatocytes and its exact mechanisms have yet to be identified. In the present study, we investigated whether quercetin directly enhanced the energy metabolism of cultured hepatocytes by focusing on lipophagy, involving selective autophagic degradation of lipid droplets. As an indicator of mitochondrial respiration, oxygen consumption was measured following 12-h treatment with quercetin or its related flavonoids, isorhamnetin and rutin (10 μM) using an extracellular flux analyzer. Treatment of alpha mouse liver 12 (AML12) hepatocytes with quercetin enhanced mitochondrial respiration, but isorhamnetin and rutin did not. Results of a palmitate-bovine serum albumin fatty acid oxidation assay showed that quercetin significantly increased the oxygen consumption of AML12 hepatocytes, suggesting enhanced fatty acid β-oxidation. However, as expression levels of mitochondrial oxidative phosphorylation proteins were unaltered by quercetin, we explored whether lipophagy contributed to enhanced fatty acid β-oxidation. Increased colocalization of lipid droplets and lysosomes confirmed that quercetin promoted lipophagy in AML12 hepatocytes. Furthermore, pharmacological inhibition of the autophagy–lysosomal pathway abolished the enhancement of fatty acid β-oxidation induced by quercetin in AML12 hepatocytes, suggesting that the enhancement of lipophagy by quercetin contributed to increased fatty acid β-oxidation. Finally, we showed that quercetin could activate AMPK signaling, which regulates autophagy even under nutrient-sufficient conditions. Our findings indicate that quercetin enhanced energy metabolism by a potentially novel mechanism involving promotion of lipophagy to produce the substrate for fatty acid β-oxidation in mitochondria through activation of AMPK signaling. Our results suggest the possibility that nutrient-induced lipophagy might contributes to the reduction of fat in hepatocytes.
Highlights
Flavonoids have been demonstrated to prevent various lifestylerelated diseases as dietary supplements [1]
As mechanistic target of rapamycin (mTOR) is a key regulator of autophagy and regulates lipid metabolism in the liver [22, 23], we hypothesized that quercetin-mediated reduction of lipid droplets in hepatocytes is related to enhanced lipophagy through the inactivation/activation of certain intracellular signaling pathways
As a novel biological activity, we recently reported that quercetin and isorhamnetin suppressed uric acid production in alpha mouse liver 12 (AML12) hepatocytes, as well as plasma and hepatic uric acid levels in a hyperuricemic model mice [26]
Summary
Flavonoids have been demonstrated to prevent various lifestylerelated diseases as dietary supplements [1]. Numerous reports have demonstrated the beneficial effect of quercetin on obesity, metabolic syndromes, and cardiovascular disorders using humans, animal models, and cultured cells. The beneficial effects of quercetin are likely caused by upregulated expression of genes related to lipid metabolism, mitochondrial biogenesis, and their accompanying transcriptional regulators [8, 9, 10]. Recent reports demonstrated that quercetin ameliorated high-fat-diet-induced NAFLD in vivo by promoting lipophagy, which involves selective autophagic degradation of lipid droplets [17, 18]. As mTOR is a key regulator of autophagy and regulates lipid metabolism in the liver [22, 23], we hypothesized that quercetin-mediated reduction of lipid droplets in hepatocytes is related to enhanced lipophagy through the inactivation/activation of certain intracellular signaling pathways
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