Abstract
Our previous study demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) has hypo-cholesterolemic and anti-obesity activity. However, the molecular mechanisms of its effects are poorly characterized. We hypothesized that 5-uRCK and one of its major bioactive compounds, ellagic acid, decrease cellular and plasma cholesterol levels. Thus, we investigated the hypocholesterolemic activity and mechanism of 5-uRCK in both hepatocytes and a high-cholesterol diet (HCD)-induced rat model. Cholesterol in the liver and serum was significantly reduced by 5-uRCK and ellagic acid. The hepatic activities of HMG-CoA and CETP were reduced, and the hepatic activity of LCAT was increased by both 5-uRCK extract and ellagic acid, which also caused histological improvements. The MDA content in the aorta and serum was significantly decreased after oral administration of 5-uRCK or ellagic acid. Further immunoblotting analysis showed that AMPK phosphorylation in the liver was induced by 5-uRCK and ellagic acid, which activated AMPK, inhibiting the activity of HMGCR by inhibitory phosphorylation. In contrast, 5-uRCK and ellagic acid suppressed the nuclear translocation and activation of SREBP-2, which is a key transcription factor in cholesterol biosynthesis. In conclusion, our results suggest that 5-uRCK and its bioactive compound, ellagic acid, are useful alternative therapeutic agents to regulate blood cholesterol.
Highlights
Hypercholesterolemia is the most important risk factor for cardiovascular disease (CVD)
Our previous study demonstrated the anti-obesity [22,23] and anti-hypercholesterolemic effects [24] of an extract of unripe R. coreanus (5-uRCK) cultivated in Korea in a high-fat diet (HFD)-fed and high-cholesterol diet (HCD)-fed mice, and we suggested that five bioactive compounds contribute to the decreased lipid accumulation in 3T3-L1 adipocytes demonstrated in another report [23]
The 5-uRCK, ellagic acid, and simvastatin groups exhibited similar effects. These results indicate that the oral administration of 5-uRCK and ellagic acid for five weeks reduced liver toxicity ellagic acid for five reduced liver toxicity in HCD-fed as a hypercholesterolemia rat model in HCD-fed rats weeks as a hypercholesterolemia rat model and wasrats safe
Summary
Hypercholesterolemia is the most important risk factor for cardiovascular disease (CVD). Aggressive diagnosis and management to lower excessive detrimental lipids are necessary [1,2]. Statins, which are 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitors, are strongly recommended for clinical treatment because of their characteristics including their high level of tolerance, various protective effects on the cardiovascular system, and ability to lower plasma low-density lipoprotein cholesterol (LDL-C) [3,4]. Some complications of statins have been reported such as muscle-related symptoms [5,6] and depression [7]. It was reported that statins do not protect against cardiovascular events in patients who are above 70 years of age [8]. The use of natural substances has been suggested as an alternative strategy for the reduction of LDL-C levels
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