Fucoxanthin from edible brown seaweeds have reported to show anti-obesity effect on diabetic/obese KK-Ay
mice and high-fat-fed C57BL/6N mice [7
]. A fucoxanthin and conjugated linolenic acid-containing supplement has also been reported to induce weight loss and reduce the body and liver fat levels in obese non-diabetic women [17
]. On the other hand, we and another group observed that fucoxanthin increases serum total cholesterol levels in rodents [5
]. Cholesterol is an important component of cell membranes and is required for the biosynthesis of bile acids and vitamin D. However, an excessive serum cholesterol level, particularly LDL cholesterol, is known to be a risk factor for atherosclerosis. Therefore, we investigated the mechanisms underlying the increase in serum cholesterol levels induced by fucoxanthin.
In this study, we observed increased HDL-cholesterol and non-HDL-cholesterol levels as well as total cholesterol levels in the serum of diabetic/obese KK-Ay mice fed fucoxanthin. Dietary fucoxanthin also significantly increased the expression of SREBP2 and SREBP1, which are key transcriptional factors involved in up-regulation of cholesterol synthesis. Further, the mRNA expression levels of HMGCR, HMGCS, FDPS, and CYP51, which are involved in cholesterol synthesis, tended to increase in the fucoxanthin-fed mice compared with the control mice, although these differences were not statistically significant. These results show that fucoxanthin slightly enhances cholesterol synthetic pathway in the liver. In contrast, hepatic cholesterol content decreased in the fucoxanthin-diet group.
To determine how fucoxanthin regulated cholesterol metabolism we considered the balance between cholesterol biosynthesis, efflux, and its incorporation in tissues. SR-B1 is known to play an important role in selectively incorporating cholesteryl esters from circulating HDL into cells. Mice with attenuated hepatic SR-B1 expression had reduced selective HDL-cholesterol clearance and increased HDL-cholesterol levels in their blood [18
]. Conversely, plasma HDL-cholesterol levels were dramatically decreased in mice that overexpressed hepatic SR-B1 [20
]. Non-HDL-cholesterol levels, mostly LDL-cholesterol levels are determined, in part, by the rate at which LDL particles are taken up and removed from the circulation by LDLR [21
]. The SR-B1 and LDLR proteins expressed in the liver at high levels and their hepatic expressions have a significant impact on circulating cholesterol levels [22
]. In the present study, fucoxanthin resulted in reduced SR-B1 and LDLR expression in the liver of the KK-Ay
mice, whereas no differences were observed in the cholesterol efflux factor ABCA1 [23
]. These results show that the increased serum cholesterol levels resulted from the reduced hepatic clearance of serum cholesterol via down-regulation of SR-B1 and LDLR by fucoxanthin. In particular, the decrease in hepatic cholesterol content suggests that the reduction of incorporation of serum cholesterol may predominate over the endogenous cholesterol biosynthesis in KK-Ay
Adipose tissue is also known to store large amounts of cholesterol and contributes to regulation of circulating cholesterol levels [24
]. Dietary fucoxanthin suppressed the enlargement of visceral WAT during the development of obesity, which resulted in attenuation of cholesterol estimations in WAT. On the other hand, dietary fucoxanthin also increased the serum cholesterol levels in non-obese ICR mice without suppressing their body weight gain [6
]. Taken together, these results suggest that the increase in serum cholesterol levels observed in the KK-Ay
mice were partly due to the suppression of fat accumulation by dietary fucoxanthin.
Thus, we have shown for the first time that dietary fucoxanthin leads to increased HDL and non-HDL-cholesterol levels in KK-Ay mice through down-regulation of hepatic LDLR and SR-B1 expression, while fucoxanthin increases the expression of SREBP2, which up-regulates LDLR. As one possible mechanism, we propose that LDLR post-transcriptional regulation is involved.
Recent studies have demonstrated LDLR post-transcriptional regulation by proprotein convertase subtilisin/kexin type 9 (PCSK9) [26
] and LXR/inducible degrader of LDLR (IDOL) signaling pathways [28
]. PCSK9 is primarily expressed in the liver, small intestine, and kidneys [29
]. PCSK9 binds to the EGF-A extracellular domain of LDLR and subsequently triggers its intracellular degradation in lysosomes [30
]. In addition, PCSK9 overexpression in mice reduced LDLR levels and increased non-HDL-cholesterol levels [31
]. Interestingly, PCSK9 has been identified as a SREBP target gene [32
]. It is noteworthy that PCSK9 mRNA expression was up-regulated by fucoxanthin. These results suggest that fucoxanthin promotes LDLR degradation through PCSK9 mRNA up-regulation in the SREBP2 signaling pathway. Additional studies are needed to elucidate the mechanism associated with PCSK9 mRNA up-regulated by fucoxanthin.
On the other hand, it has been reported that hepatic SR-B1 expression is regulated by a variety of dietary components, hormonal, metabolic, and pharmacological manipulations [22
]. Nuclear receptors components such as liver X receptor (LXR) and peroxisome proliferator-activated receptor-α (PPARα) are also known to regulate hepatic SR-B1 expression [35
]. In this study, we could not identify a key factor to suppress SR-B1 by fucoxanthin. Further investigation is required to clarify the effect of fucoxanthin on SR-B1 expression.
In this study, we showed for the first time that dietary fucoxanthin resulted in increased serum HDL and non-HDL-cholesterol levels as well as total cholesterol levels via the activation of SREBP signaling and by suppressing serum cholesterol uptake in the liver via decreasing LDLR and SR-B1 expression. Further, our results suggest that LDLR degradation is promoted by fucoxanthin through up-regulation of PCSK9 and leads to increased non-HDL-cholesterol levels. These findings provide important insights on the effects of fucoxanthin on cholesterol and lipoprotein metabolism. However, it is unclear whether the responses to cholesterol metabolism are specific for rodents or common to human. Dysfunction of cholesterol metabolism is strongly associated with arteriosclerosis. Therefore, it will be necessary to further investigate the influence of high serum cholesterol levels induced by fucoxanthin on human health.