AMPK has critical roles in energy metabolism including cholesterol biosynthesis and autophagy pathway. This study investigated hypocholesterolemic and hypolipidemic effects of hexacosanol which is a long chain alcohols extracted from plant waxes through AMPK dependent pathways. Hexacosanol revealed ...
AMPK has critical roles in energy metabolism including cholesterol biosynthesis and autophagy pathway. This study investigated hypocholesterolemic and hypolipidemic effects of hexacosanol which is a long chain alcohols extracted from plant waxes through AMPK dependent pathways. Hexacosanol revealed direct and dose-dependent activation of AMPK by in vitro kinase activity assay. Active AMPK stimulates HMGCR phosphorylation that inhibits HMGCR activity thus reduces cholesterol biosynthesis. Consequently, HepG2 cells stimulated with hexacosanol significantly decreased total, free cholesterol and cholesteryl ester concentrations. Administration of hexacosanol also showed reduction of plasma and hepatic cholesterol concentrations in high fat fed C57BL6J mice. Moreover, hexacosanol lowered cholesterol accumulation by regulation of CYP7A1 and ACAT2 which are genes in bile acid and cholesteryl ester synthesis, respectively. Hepatic autophagy was stimulated with hexacosanol with induced protein expressions of LC3II and LAMP that removes hepatic lipids. In conclusion, hexacosanol improves symptoms of hypercholesterolemia and hepatic steatosis by activating AMPK and induction of hepatic autophagy.Flavonoids are plant secondary metabolites and generally exhibit as pigments in the flower and fruits. In this study, hypoglycemic effect of saponarin, which is a flavonoid found in high concentrations in barley sprout was investigated. Glucose homeostasis is maintained by AMP-activated protein kinase (AMPK) and its downstream target proteins. Interestingly, saponarin could not directly activate the AMPK, but increased cellular calcium concentration, which can promote AMPK upstream kinase, Calcium/calmodulin-dependent protein kinase-β (CAMKK-β) then regulates its downstream genes. In HepG2, AMPK inhibits translocation of histone deacetylases-5 (HDAC5) and cyclic AMP-responsive element-binding protein (CREB) regulated transcription coactivator-2 (CRTC2), which are the coactivators for forkhead box O1 (FOXO1) and CREB, respectively. Finally, these enzymes suppress the transcription of gluconeogenic enzymes including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In TE671 cells, AMPK also inhibits HDAC5 from nuclear penetration, thus activating the glucose transporter-4 (GLUT4) transcription level to enhance glucose uptake by myocytes. In conclusion, saponarin activates AMPK, resulting in hypoglycemic activities and improvements in insulin sensitivity.AMP-activated protein kinase (AMPK) and sterol-regulatory element-binding protein-2 (SREBP2) are major regulators of hepatic glucose and cholesterol homeostasis. The active AMPK phosphorylates and inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) activity, and SREBP2 regulates HMGCR transcription. AMPK also regulates hepatic gluconeogenic gene expressions, thus lowers fasting plasma glucose concentrations and improves insulin sensitivity. This study investigated the mechanism of barley sprout (BS) and its two major bioactive compounds, hexacosanol and saponarin, on cholesterol and glucose metabolism in cultured hepatocytes and high-fat-diet fed mice. BS significantly reduced hepatic cholesterol concentrations with the activation of AMPK and subsequent induction of HMGCR phosphorylation. BS also suppressed nuclear translocation of SREBP2, thus, reduced HMGCR transcription. Hexacosanol regulated cholesterol biosynthesis with the similar mechanisms mediated by BS. Activation of hepatic autophagy was confirmed with protein expressions of LC3-II and LAMP that reduced hepatic triglyceride concentrations in BS and hexacosanol fed mice. In addition, AMPK activation with BS reduced fasting glucose in mice by repressing the hepatic gluconeogenic genes including fructose-1, 6-bisphosphatase and pyruvate carboxylase. In the same manner, inhibition of hepatic gluconeogenesis and induction of glucose uptake in myocytes were achieved in cells stimulated with saponarin, a key flavonoid of BS. Collectively, these results demonstrate appropriate intake of BS may have hypocholesterolemic and hypoglycemic activities to ameliorate hepatic steatosis. Hexacosanol and saponarin may be key effective compounds.Mechanism of barley sprout (BS), which is enriched with policosanols and polyphenols, on cholesterol and glucose metabolism was investigated. BS reduced the intracellular cholesterol concentrations in the HepG2 cells and the plasma cholesterol concentrations in the mice by the activation of AMPK and the subsequent phosphorylation inhibition of HMGCR. BS suppressed the nuclear translocation of SREBP2, reducing the transcription of HMGCR. AMPK activation with BS reduced the fasting glucose and hepatic triglyceride concentrations in mice by repressing the hepatic gluconeogenic genes, including fructose-1, 6-bisphosphatase and pyruvate carboxylase and the plasma levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6. The activation of hepatic autophagy by BS was confirmed by induced protein expressions of LC3-II and LAMP. In conclusion, BS activates AMPK and hepatic autophagy and inhibits SREBP2, resulting in hypocholesterolemic and hypoglycemic activities and improvements in the symptoms of hepatic steatosis.
AMPK has critical roles in energy metabolism including cholesterol biosynthesis and autophagy pathway. This study investigated hypocholesterolemic and hypolipidemic effects of hexacosanol which is a long chain alcohols extracted from plant waxes through AMPK dependent pathways. Hexacosanol revealed direct and dose-dependent activation of AMPK by in vitro kinase activity assay. Active AMPK stimulates HMGCR phosphorylation that inhibits HMGCR activity thus reduces cholesterol biosynthesis. Consequently, HepG2 cells stimulated with hexacosanol significantly decreased total, free cholesterol and cholesteryl ester concentrations. Administration of hexacosanol also showed reduction of plasma and hepatic cholesterol concentrations in high fat fed C57BL6J mice. Moreover, hexacosanol lowered cholesterol accumulation by regulation of CYP7A1 and ACAT2 which are genes in bile acid and cholesteryl ester synthesis, respectively. Hepatic autophagy was stimulated with hexacosanol with induced protein expressions of LC3II and LAMP that removes hepatic lipids. In conclusion, hexacosanol improves symptoms of hypercholesterolemia and hepatic steatosis by activating AMPK and induction of hepatic autophagy.Flavonoids are plant secondary metabolites and generally exhibit as pigments in the flower and fruits. In this study, hypoglycemic effect of saponarin, which is a flavonoid found in high concentrations in barley sprout was investigated. Glucose homeostasis is maintained by AMP-activated protein kinase (AMPK) and its downstream target proteins. Interestingly, saponarin could not directly activate the AMPK, but increased cellular calcium concentration, which can promote AMPK upstream kinase, Calcium/calmodulin-dependent protein kinase-β (CAMKK-β) then regulates its downstream genes. In HepG2, AMPK inhibits translocation of histone deacetylases-5 (HDAC5) and cyclic AMP-responsive element-binding protein (CREB) regulated transcription coactivator-2 (CRTC2), which are the coactivators for forkhead box O1 (FOXO1) and CREB, respectively. Finally, these enzymes suppress the transcription of gluconeogenic enzymes including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In TE671 cells, AMPK also inhibits HDAC5 from nuclear penetration, thus activating the glucose transporter-4 (GLUT4) transcription level to enhance glucose uptake by myocytes. In conclusion, saponarin activates AMPK, resulting in hypoglycemic activities and improvements in insulin sensitivity.AMP-activated protein kinase (AMPK) and sterol-regulatory element-binding protein-2 (SREBP2) are major regulators of hepatic glucose and cholesterol homeostasis. The active AMPK phosphorylates and inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) activity, and SREBP2 regulates HMGCR transcription. AMPK also regulates hepatic gluconeogenic gene expressions, thus lowers fasting plasma glucose concentrations and improves insulin sensitivity. This study investigated the mechanism of barley sprout (BS) and its two major bioactive compounds, hexacosanol and saponarin, on cholesterol and glucose metabolism in cultured hepatocytes and high-fat-diet fed mice. BS significantly reduced hepatic cholesterol concentrations with the activation of AMPK and subsequent induction of HMGCR phosphorylation. BS also suppressed nuclear translocation of SREBP2, thus, reduced HMGCR transcription. Hexacosanol regulated cholesterol biosynthesis with the similar mechanisms mediated by BS. Activation of hepatic autophagy was confirmed with protein expressions of LC3-II and LAMP that reduced hepatic triglyceride concentrations in BS and hexacosanol fed mice. In addition, AMPK activation with BS reduced fasting glucose in mice by repressing the hepatic gluconeogenic genes including fructose-1, 6-bisphosphatase and pyruvate carboxylase. In the same manner, inhibition of hepatic gluconeogenesis and induction of glucose uptake in myocytes were achieved in cells stimulated with saponarin, a key flavonoid of BS. Collectively, these results demonstrate appropriate intake of BS may have hypocholesterolemic and hypoglycemic activities to ameliorate hepatic steatosis. Hexacosanol and saponarin may be key effective compounds.Mechanism of barley sprout (BS), which is enriched with policosanols and polyphenols, on cholesterol and glucose metabolism was investigated. BS reduced the intracellular cholesterol concentrations in the HepG2 cells and the plasma cholesterol concentrations in the mice by the activation of AMPK and the subsequent phosphorylation inhibition of HMGCR. BS suppressed the nuclear translocation of SREBP2, reducing the transcription of HMGCR. AMPK activation with BS reduced the fasting glucose and hepatic triglyceride concentrations in mice by repressing the hepatic gluconeogenic genes, including fructose-1, 6-bisphosphatase and pyruvate carboxylase and the plasma levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6. The activation of hepatic autophagy by BS was confirmed by induced protein expressions of LC3-II and LAMP. In conclusion, BS activates AMPK and hepatic autophagy and inhibits SREBP2, resulting in hypocholesterolemic and hypoglycemic activities and improvements in the symptoms of hepatic steatosis.
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