Abstract
High blood cholesterol has been associated with cardiovascular diseases. The enzyme HMG CoA reductase (HMGCR) is responsible for cholesterol synthesis, and inhibitors of this enzyme (statins) have been used clinically to control blood cholesterol. Sterol regulatory element binding protein (SREBP) -2 is a key transcription factor in cholesterol metabolism, and HMGCR is a target gene of SREBP-2. Attenuating SREBP-2 activity could potentially minimize the expression of HMGCR. Luteolin is a flavone that is commonly detected in plant foods. In the present study, Luteolin suppressed the expression of SREBP-2 at concentrations as low as 1 μM in the hepatic cell lines WRL and HepG2. This flavone also prevented the nuclear translocation of SREBP-2. Post-translational processing of SREBP-2 protein was required for nuclear translocation. Luteolin partially blocked this activation route through increased AMP kinase (AMPK) activation. At the transcriptional level, the mRNA and protein expression of SREBP-2 were reduced through luteolin. A reporter gene assay also verified that the transcription of SREBF2 was weakened in response to this flavone. The reduced expression and protein processing of SREBP-2 resulted in decreased nuclear translocation. Thus, the transcription of HMGCR was also decreased after luteolin treatment. In summary, the results of the present study showed that luteolin modulates HMGCR transcription by decreasing the expression and nuclear translocation of SREBP-2.
Highlights
Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide
As previous studies have shown that protein kinases might participate in the processing and activation of sterol-regulatory element binding protein (SREBP)-2, we examined the status of some protein kinases under luteolin treatment
We demonstrated that the Sterol Responsive Element (SRE)-binding activity and pJNK in hepatic cells were reduced through luteolin as two potential mechanisms for the suppression of SREBF2 mRNA expression
Summary
Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide. Serum cholesterol levels are correlated with the risk of CVD. A recent meta-analysis estimated that a decrease of 10 mg/dl plasma cholesterol could reduce the mortality of coronary heart disease by 9% in the elderly [1]. Cholesterol homeostasis is tightly controlled in humans. Luteolin Reduces Active SREBP-2 in Liver Cells through the sterol-regulatory element binding protein (SREBP). SREBP-2 regulates HMG-CoA reductase (HMGCR) expression, which catalyzes the rate-limiting step of cholesterol biosynthesis. HMGCR inhibitors have been prescribed clinically for the treatment of patients with hypercholesterolemia. Influencing HMGCR activity through SREBP-2 could be an alternative approach for treating this disease
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