Health benefits of fucoxanthin in the prevention of chronic diseases

Journal Pre-proof Health benefits of fucoxanthin in the prevention of chronic diseases

Minkyung Bae, Mi-Bo Kim, Young-Ki Park, Ji-Young Lee PII:

S1388-1981(20)30010-X

DOI:

https://doi.org/10.1016/j.bbalip.2020.158618

Reference:

BBAMCB 158618

To appear in:

BBA - Molecular and Cell Biology of Lipids

Received date:

6 November 2019

Revised date:

5 January 2020

Accepted date:

7 January 2020

Please cite this article as: M. Bae, M.-B. Kim, Y.-K. Park, et al., Health benefits of fucoxanthin in the prevention of chronic diseases, BBA - Molecular and Cell Biology of Lipids(2020), https://doi.org/10.1016/j.bbalip.2020.158618

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© 2020 Published by Elsevier.

Journal Pre-proof Health benefits of fucoxanthin in the prevention of chronic diseases

Minkyung Bae1, Mi-Bo Kim1, Young-Ki Park1, Ji-Young Lee1,2 1

Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut 06269,

USA Corresponding author: Ji-Young Lee, Ph.D. Fax: (860) 486-3674

Email: [email protected]

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Phone: (860) 486-2242

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Running title: The health benefits of fucoxanthin

Abbreviations: AMPK, AMP-activated protein kinase; CPT-1, carnitine palmitoyl transferase 1;

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C/EBPα, CCAAT/enhancer-binding protein alpha; CDK, cyclin-dependent kinase; COX-2,

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cyclooxygenase-2; FAS, fatty acid synthase; Fe-NTA, ferric nitrilotriacetate; G6PD, glucose-6-

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phosphate dehydrogenase; GLUT4, glucose-transporter 4; GPDH, glycerol-3-phosphate dehydrogenase; HSCs, hepatic stellate cells; iNOS, inducible nitric oxide synthase; IL-1β,

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interleukin-1β; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; ME,

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malic enzyme; MMP, matrix metalloproteinase; NO, nitric oxide; NAFLD, nonalcoholic fatty liver disease; NF-κB, nuclear factor-κB; PI3K, phosphatidylinositol-3-kinase; PPARα, peroxisome proliferator-activated receptor α; PGE2, prostaglandin E2; ROS, reactive oxygen species; SR-BI, scavenger receptor class B, type 1; SREBP-1c, sterol regulatory element-binding protein 1c; TGFβ1, transforming growth factor β1; TNF-α, tumor necrosis factor-α; UCP-1, uncoupling protein 1

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Journal Pre-proof Abstract Fucoxanthin is a xanthophyll carotenoid abundant in macroalgae, such as brown seaweeds. When fucoxanthin is consumed, it can be esterified or hydrolyzed to fucoxanthinol in the gastrointestinal tract and further converted into amarouciaxanthin A in the liver. It has a unique chemical structure that confers its biological effects. Fucoxanthin has a strong antioxidant capacity by scavenging singlet molecular oxygen and free radicals. Also, it exerts an anti-

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inflammatory effect. Studies have demonstrated potential health benefits of fucoxanthin for the

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prevention of chronic diseases, such as cancer, obesity, diabetes mellitus, and liver disease.

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Animal studies have shown that fucoxanthin supplementation has no adverse effects. However,

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investigation of the safety of fucoxanthin consumption in humans is lacking. Clinical trials are required to assess the safety of fucoxanthin in conjunction with the study of mechanisms by

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which fucoxanthin exhibits its health benefits. This review focuses on current knowledge of

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metabolism and functions of fucoxanthin with its potential health benefits.

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Keywords: Fucoxanthin; Carotenoid; Brown seaweed; Antioxidant; Anti-inflammation

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Journal Pre-proof Introduction Fucoxanthin is a xanthophyll carotenoid abundant in macroalgae, such as brown seaweeds, and microalgae [1]. Several edible brown algae, including Sargassam fusiforme, Laminaria japonica, Undaria pinnatifida, and Padina tetrastromatica, are consumed in SouthEast Asia and European countries [2]. The brown algae are good sources of fucoxanthin [3], however, diatoms, such as Phaeodactylum tricornutum, are preferred sources of fucoxanthin in

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the food industry because of their higher fucoxanthin content and extraction efficiency with

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shorter growth cycle than those of macroalgae [4].

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Fucoxanthin has a unique chemical structure that contains an allenic bond, epoxy,

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hydroxyl, carbonyl, and carboxyl groups in the molecule (Figure 1). Among ~700 carotenoids found in nature, only about 40 carotenoids have an allenic bond [3], which may confer a free

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radical scavenging activity [5]. It is known that fucoxanthin has a potent antioxidant capacity by

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scavenging singlet molecular oxygen and free radicals [6]. However, fucoxanthin is unstable, and it can be easily degraded by heating, aerial exposure, or illumination [7].

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The primary metabolites of fucoxanthin are fucoxanthinol and amarouciaxanthin A.

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Fucoxanthin can be hydrolyzed to fucoxanthinol in the gastrointestinal tract and further converted into amarouciaxanthin A in the liver (Figure 2) [8, 9]. [8]In animal studies, no toxicity of fucoxanthin was observed [12, 13]. Although clinical trials of fucoxanthin supplementation to assess its safety are lacking, the Food and Drug Administration allowed fucoxanthin extracted from alga, Phaeodactylum tricornutum, as a new dietary ingredient that can be consumed at a level of 3 mg daily with no time limit or 5 mg fucoxanthin daily for up to 90 days [14]. Studies have demonstrated that fucoxanthin may be used to prevent or treat chronic diseases, such as obesity, diabetes mellitus, and cancer. This review summarizes current

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Journal Pre-proof knowledge of functions and potential health benefits of fucoxanthin, including anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, and hepatoprotective effects.

Chemical structure and antioxidant capacity Fucoxanthin is one of the carotenoids that contain an allenic bond in their molecules [11]. The major allenic carotenoids include fucoxanthin in brown algae or diatoms, peridinin in

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dinoflagellates, and neoxanthin in plants and algae [15]. In addition to an allenic bond,

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fucoxanthin has epoxy, hydroxyl, carbonyl, and carboxyl groups [16].

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Carotenoids, including fucoxanthin, are known to have an antioxidant capacity that can

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scavenge singlet molecular oxygen (1O2) and peroxyl radicals [17]. Singlet oxygen quenching by carotenoids mostly depends on physical quenching, i.e., transferring energy between two

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molecules [17, 18]. The energy of singlet oxygen is transferred to conjugated double bonds in the

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central chain of carotenoids [11], leading to a triplet unreactive ground state of oxygen and a triplet excited state of the carotenoid molecules. The excited carotenoids return to a ground state

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by dissipating energy into the environment. During physical quenching, there are no chemical

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reactions between singlet molecular oxygen and a carotenoid. Thus, carotenoids are not oxidized or consumed by the reaction, and therefore they can be reused. The efficiency of singlet oxygen quenching by carotenoids increases with the number of conjugated double bonds [19]. Carotenoids also scavenge free radicals. The ability of carotenoids to scavenge free radicals depends on the presence of functional groups with increasing polarity, such as carbonyl and hydroxyl groups, in their terminal rings [20]. Studies have demonstrated that fucoxanthin decreases intracellular reactive oxygen species (ROS) levels, lipid peroxidation, and protein carbonyl contents that are induced by ferric nitrilotriacetate in murine embryonic hepatic BNL

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Journal Pre-proof CL.2 cells [21]. Also, fucoxanthin decreases malondialdehyde levels in tributyltin-treated HepG2 cells, thus increasing cell viability [22]. In addition, fucoxanthin is known to improve the cell’s endogenous antioxidant defense system. Fucoxanthin increased mRNA and protein levels of glutamate-cysteine ligase catalytic subunit and glutathione synthetase, which are involved in glutathione synthesis, in human keratinocyte cell line HaCaT cells [23]. Furthermore, fucoxanthin markedly increased the

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nuclear protein level of nuclear factor-erythroid 2 related factor 2, a transcription factor that

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regulates the expression of several antioxidant proteins, such as heme oxygenase-1 and

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NAD(P)H: quinine oxidoreductase 1, in mouse hepatic BNL CL.2 cells [24].

Metabolism of fucoxanthin

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Digestion, absorption, and transport of fucoxanthin

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Carotenoids are absorbed in the small intestine, similar to dietary lipids and lipid-soluble vitamins [25]. It is known that carotenoid absorption occurs in the proximal half of the small

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intestine [26]. For the intestinal absorption of carotenoids, there are several essential steps.

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Carotenoids should be released from the food matrix to be solubilized into mixed lipid micelles in the lumen for the entry into intestinal mucosal cells [27]. It has been suggested that carotenoids are absorbed into the enterocyte via facilitated diffusion through scavenger receptor class B, type 1 (SR-BI) [28]. Although not proven, SR-BI is a plausible carrier of fucoxanthin for its intestinal absorption. It has been demonstrated that fucoxanthin is esterified in human intestinal Caco-2 cells [10]. Therefore, esterified fucoxanthin is likely incorporated into chylomicrons with lipids similarly to other carotenoids for the systemic transport.

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Journal Pre-proof Fucoxanthin metabolites When fucoxanthin is consumed, it can be esterified [10] or hydrolyzed to fucoxanthinol in the gastrointestinal tract by cholesterol esterase and lipase [8]. Fucoxanthinol can be further metabolized into amarouciaxanthin A through dehydrogenation and isomerization in the liver [9]. In a pharmacokinetic study, when a single dose of fucoxanthin (65 mg/kg body weight) was administered to rats, fucoxanthin was detected in the circulation at 30 min post-administration

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and it reached its maximal concentration of 29 µg/L at ~8 h, while the level of fucoxanthinol in

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plasma was its maximum of 263 µg/L at 11 h after fucoxanthin administration [30]. The data

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indicate that large amount of fucoxanthin is converted into fucoxanthinol in the intestine.

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In humans, after a single oral administration of 31 mg fucoxanthin [31] or daily consumption of 6.1 mg fucoxanthin for a week [32], fucoxanthinol, but not amarouciaxanthin A,

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was detected in the circulation. In mice, however, studies have shown that both fucoxanthinol

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and amarouciaxanthin A were detected in plasma [8] and tissues, including the liver [9, 33, 34]. It may be due to the difference in fucoxanthin metabolism between humans and mice, as mice

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potentially metabolize and eliminate fucoxanthin faster than humans [31], which should be

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considered when conducting studies for the effect of fucoxanthin in mice. In a pharmacokinetic study, fucoxanthinol and amarouciaxanthin A, but not fucoxanthin, were detected in the plasma, erythrocytes, liver, lung, kidney, heart, spleen, and adipose tissue when mice were orally administered with 160 nmol fucoxanthin [34]. After daily oral administration of fucoxanthin (160 nmol/day) for a week, fucoxanthin and its metabolites, i.e., fucoxanthinol and amarouciaxanthin A, were detected in tissue, but fucoxanthin was not present in the plasma. Consistently, after dietary fucoxanthin supplementation (0.128 ± 0.016 µmol/day) for 14 days, fucoxanthinol and amarouciaxanthin A were found in adipose tissues as well as in the plasma,

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Journal Pre-proof liver, and kidney [35]. Therefore, fucoxanthin and its metabolites are delivered to different tissues to exert their biological effects with the metabolites being predominant forms [31, 34].

Safety and toxicity Studies have been conducted to assess the safety of fucoxanthin in vivo. A single oral administration of fucoxanthin at a dose of 1000 or 2000 mg/kg body weight did not elicit any

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mortality and abnormality in ICR mice [12]. In addition, orally-administered fucoxanthin at a

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dose of 500 or 1000 mg/kg body weight for 30 days did not induce abnormal changes in tissues,

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including the liver, kidney, spleen, and gonadal tissues in ICR mice [12]. In rats administered

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with a single oral dose of 2000 mg fucoxanthin/kg body weight or with 20 or 200 mg fucoxanthin/kg body weight for 13 weeks, no evident mortality or abnormalities were observed

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[13]. Therefore, it appears that fucoxanthin consumption is safe at least in the experimental

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animal models.

The amount of fucoxanthin in brown seaweeds varies from 172 to 720 mg/kg dry weight [36],

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which is a relatively small amount compared with the doses of fucoxanthin administered in the

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aforementioned animal studies. In addition, a dose of 2000 mg fucoxanthin/kg body weight in mice is equivalent to ~162 mg/kg body weight in humans, which may not be easily attainable by the consumption of seaweeds or dietary supplements in humans. Although the high amount of fucoxanthin seems to be safe in rodents, the safety investigation of fucoxanthin in humans is very limited. Ren et al. [37] administered human subjects with 5 mg of fucoxanthin/day for 5 weeks and the dose did not induce any adverse side effects. Fucoxanthin supplementation (1.6, 2.4, 4, or 8 mg) three times a day for 16 weeks showed no adverse effects in obese female subjects [38]. Two clinical trials are currently registered at the U. S. National Library of Medicine to determine

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Journal Pre-proof the health benefits of daily 12 mg fucoxanthin consumption for 90 days (ClinicalTrials.gov Identifier: NCT03613740) [39] and daily 1650 mg fucoxanthin for up to 6 months (ClinicalTrials.gov Identifier: NCT02875392) [40]. More clinical trials are required to determine the safety and effective supplementation levels of fucoxanthin in humans.

Health benefits of fucoxanthin

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Anti-inflammatory effect

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Inflammation is a biological process of the immune system in response to various

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external stimuli, including pathogens and toxic compounds, to counteract the inflammatory

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insults [41]. Although inflammation is a crucial for the host defense, dysregulation of inflammatory responses leads to chronic inflammation, which is closely related to the

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pathogenesis of various diseases, including cardiovascular disease, diabetes, metabolic syndrome,

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inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive lung disease, and cancer [42]. Therefore, it is essential to inhibit chronic inflammation for the prevention of the

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diseases mentioned above.

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Studies have shown that fucoxanthin exerts anti-inflammatory action in vitro and in vivo. Fucoxanthin reduced the production of pro-inflammatory mediators, such as prostaglandin E2 (PGE2) and nitric oxide (NO), in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages [43, 44] and in LPS-treated BV-2 microglial cells [45]. This effect of fucoxanthin was attributed to its capacity to decrease protein levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). In addition, the production of pro-inflammatory cytokines, such as interleukin1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα), was significantly decreased by fucoxanthin in LPS-treated RAW 264.7 macrophages [43, 44] and in LPS-treated BV-2

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Journal Pre-proof microglial cells with a concomitant decrease in cellular ROS levels [45]. The anti-inflammatory effect of fucoxanthin is likely due to its inhibitory effect on the activation of nuclear factor-κB (NF-κB) and the phosphorylation of mitogen-activated protein kinases, including c-JUN Nterminal kinase, extracellular signal-regulated kinase, and p38, in RAW 264.7 macrophages [46] and BV-2 microglial cells [45]. The anti-inflammatory properties of fucoxanthin have also been demonstrated in vivo.

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Fucoxanthin supplementation at 0.6% by weight for 4 weeks significantly decreased serum

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levels of IL-1β and TNFα in mice fed a high-fat diet [47]. Also, dietary supplementation of

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fucoxanthin in a chow diet reduced the expression of TNFα and monocyte chemoattractant

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protein-1 (MCP-1) in the white adipose tissue of KK-Ay mice [48]. In a mouse model of colitis, oral administration of fucoxanthin at a dose of 50 or 100 mg/kg body weight/day for 7 days

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ameliorated damages in the colon with reductions in PGE2 levels and COX-2 and NF-κB mRNA

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and protein [49]. A recent study has shown that intragastric administration of fucoxanthin (200 mg/kg body weight) for 7 days before LPS injection to induce behavioral defects in mice

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improved depression and anxiety [50]. In this study, fucoxanthin reduced the protein level of

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pro-inflammatory cytokines and enzymes, such as IL-1β, IL-6, and TNFα, iNOS, and COX-2, in the hippocampus, frontal cortex, and hypothalamus with a concomitant increase in phosphorylation of AMP-activated protein kinase (AMPK) and a decrease in NF-κB p65 protein. Furthermore, intravenous injection of fucoxanthin at a daily dose of 0.5 or 5 mg/kg body weight for 7 days improved ultraviolet B irradiation-induced corneal disorders in rats [51]. Importantly, protein levels of TNFα and vascular endothelial growth factor and infiltration of polymorphonuclear leukocytes in corneal tissues were decreased by fucoxanthin, suggesting that

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Journal Pre-proof anti-inflammatory properties of fucoxanthin likely contribute to the prevention of corneal disorders.

Anti-cancer effect Cancer is the second leading cause of death, with an estimated 9.6 million deaths in 2018 worldwide [52]. Lung cancer is the most common cancer in both sexes, followed by breast

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cancer in female, prostate cancer in male, and colorectal cancer [53]. Moreover, the most

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common cause of death related to cancer is also lung cancer, which is followed by colorectal,

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stomach, and liver cancer [53]. The diagnosis of cancer in the early stage is crucial to reduce

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cancer-related death.

The preventive effect of fucoxanthin on cancer has been suggested in several cancer

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models. The anti-cancer effects of fucoxanthin are mediated by inducing cell cycle arrest and

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apoptosis while inhibiting metastasis. Inhibiting the progression of the cell cycle is essential for cancer therapy [54]. Fucoxanthin is shown to reduce cell viability or proliferation by inducing

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cell cycle arrest in human gastric adenocarcinoma SGC-7901 and BGC-823 cells [55], human

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non-small cell lung cancer cells, including A549 and H1299 [56], and the human bladder cancer T24 cell line [57]. The inhibitory effect of fucoxanthin on cell proliferation was mediated by increased p21, a cyclin-dependent kinase (CDK)-inhibitory protein, and decreased CDK-2, CDK-4, cyclin D1, and cyclin E in human bladder cancer T24 cell line. In addition, fucoxanthin can induce apoptosis of cells by increasing the expression of Bax while decreasing Bcl-2 expression in human cervical cancer SiHa cells [58], human gastric cancer cell line SGC7901 cells [59], human non-small cell lung cancer cells, including A549 and H1299 [56], human glioma cancer cell line U87 and U251 cells [60], and human bladder cancer

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Journal Pre-proof cell line T24 cells [57]. Fucoxanthin also increased caspase-3 activity in these cancer cells. The effect of fucoxanthin on the induction of apoptotic cell death was mediated by inhibition of the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt)/ mechanistic target of rapamycin pathway in cancer cells [60-62]. In addition, fucoxanthin induces apoptosis by reducing mRNA and protein expression of myeloid cell leukemia 1, an anti-apoptotic protein, signal transducer and activator of transcription 3 (STAT3), a transcription factor repressing apoptosis, and

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phosphorylated active form of STAT3 in human gastric adenocarcinoma SGC-7901 or BGC-823

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cells [55]. In DLD-1 cells, fucoxanthin induces anoikis, which is apoptosis induced by cell

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detachment [63]. The effect of fucoxanthin on apoptosis in cancer cells was also demonstrated in

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vivo. Fucoxanthin administration inhibited polyp formation and increased anoikis-like cells in colonic mucosa of mice treated with azoxymethane and dextran sodium sulfate for the induction

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of colorectal tumors [63].

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The anti-cancer effect of fucoxanthin is also mediated by the inhibition of cancer cell migration or invasion. Fucoxanthin attenuated the migration of U87 and U251 cells in vitro,

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which was measured by the scratch wound healing assay and invasion of the cells through the

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matrigel membrane using the trans-well assay [60]. In U87 and U251 cells, fucoxanthin decreased protein levels of matrix metalloproteinases 2 (MMP-2) and MMP-9 [60], which play a crucial role in tumor invasion and metastasis [64]. Fucoxanthin also reduced migration and invasion of highly metastatic murine B16-F10 melanoma cells, which was attributed to a reduction in the formation of actin fibers and the expression of MMP-9 in B16-F10 cells [65].

Anti-obesity effect

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Journal Pre-proof Consumption of a diet high in fat and a lack of exercise cause an imbalance between energy intake and expenditure, leading to excessive accumulation of visceral fat. Obese individuals have high risks of developing type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease, and other metabolic and inflammatory diseases [66, 67]. As these diseases increase mortality worldwide, it is essential to find strategies for preventing or treating obesity.

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Studies have evaluated an anti-obesogenic effect of fucoxanthin. In db/db diabetic mice,

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fucoxanthin supplementation at 0.2% or 0.4% by weight for 6 weeks reduced plasma triglyceride

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and total cholesterol concentrations, which was attributed to the upregulation of hepatic protein

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expression of peroxisome proliferator-activated receptor α (PPARα), phosphorylated acetylcoenzyme A carboxylase, and carnitine palmitoyltransferase 1 (CPT-1) [68]. Fucoxanthin also

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downregulated fatty acid synthase (FAS) protein via the activation of AMPK in the liver.

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Moreover, in obese rats, daily administration of fucoxanthin (1 mg/kg body weight) for 8 weeks significantly improved serum lipid profiles, i.e., decreases in triglycerides, total cholesterol, and

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low-density lipoprotein cholesterol with increased high-density lipoprotein cholesterol [69]. The

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changes in serum lipids were likely due to the upregulation of genes associated with energy expenditure and fatty acid oxidation, including PPARα and PPARγ coactivator 1α, in adipose tissue and the liver. Furthermore, when mice were fed a high-fat diet supplemented with fucoxanthin (0.05% or 0.2%, w/w) for 6 weeks, fucoxanthin significantly reduced fat-pad weight and adipocyte size [70]. This effect of fucoxanthin was attributed to the downregulation of mRNA and activity of lipogenic enzymes, including FAS, glucose-6-phosphate dehydrogenase (G6PD), and malic enzyme (ME) while upregulating genes involved in fatty acid β‐ oxidation. Gille et al. [71] also reported that consumption of fucoxanthin-rich extract (300 mg/kg body

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Journal Pre-proof weight/day) from Phaeodactylum tribornutum for 26 days reduced body weight gain and white adipose tissue weight in mice fed a high-fat diet. Uncoupling protein 1 (UCP-1), a thermogenic mitochondrial protein, is usually expressed in brown adipose tissue. However, UCP-1 expression in white adipose tissue can be induced, leading to browning of white adipose tissue, consequently increasing thermogenesis [72, 73]. Studies have demonstrated that fucoxanthin stimulates UCP-1 expression in white adipose tissue.

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Mice fed a fucoxanthin-rich fraction from edible seaweed, Undaria pinnatifida, showed a

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significant increase in UCP-1 expression in white adipose tissue concomitantly with decreased

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white adipose tissue weight [74]. Furthermore, consumption of AIN-93G diet containing fucoxanthin (0.2%, w/w) for 4 weeks significantly reduced white adipose tissue weight gain with

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the induction of UCP-1 expression in diabetic/obese KK-Ay mice [75]. Also, when a high-fat diet

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containing 0.05% fucoxanthin (w/w) was given to mice for 6 weeks, there was a significant

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increase in UCP-1 expression, which was likely to contribute to increased fatty acid β-oxidation and decreased fat production in white adipose tissue [70]. The expression of UCP-1 was

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increased in the subcutaneous white adipose tissues of mice fed a high-fat diet containing

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fucoxanthin-rich extract [71]. Therefore, several studies have linked the anti-obesity effect of fucoxanthin to the induction of UCP-1 and beiging (or browing) of white adipose tissue. However, Rebello et al.[76] reported that fucoxanthin and fucoxanthinol did induce the browning of human adipocytes. Therefore, further studies are required to determine the effect of fucoxanthin on adipose tissue browning. Studies have also demonstrated that the anti-obesity effect of fucoxanthin is mediated, at least partly, by inhibiting adipocyte differentiation. Fucoxanthin significantly suppressed lipid accumulation during adipogenesis, which was mediated by inhibiting the expression of

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Journal Pre-proof adipogenic and lipogenic factors, such as CCAAT/enhancer-binding protein alpha (C/EBPα), PPARγ, fatty acid-binding protein 4, diglyceride acyltransferase 1, and lysophosphatidic acid acyltransferase-θ in 3T3-L1 adipocytes [77]. The progression of adipocyte differentiation in 3T3L1 preadipocyte has three stages, i.e., early (days 0-2), intermediate (days 2-4), and late (days 47) [78]. Fucoxanthin showed different effects on adipocyte differentiation at each stage of differentiation. For instance, fucoxanthin promoted adipocyte differentiation at the early stage

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while it suppressed at the later stage. At the early stage of adipocyte differentiation in 3T3-L1

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cells, fucoxanthin dose-dependently increased the protein levels of PPARγ, C/EBPα, and sterol

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regulatory element-binding protein 1c (SREBP-1c), while it inhibited the protein levels during

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the intermediate and late stages of differentiation [78]. Furthermore, fucoxanthin and its metabolite, fucoxanthinol, showed an inhibitory effect on adipocyte differentiation in 3T3-L1

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adipocyte, as evidenced by reduced intracellular lipid accumulation and glycerol-3-phosphate

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dehydrogenase (GPDH) activity, which was attributed to the downregulation of PPARγ expression [79]. Fucoxanthinol exhibited stronger inhibitory effects on adipocyte differentiation

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than fucoxanthin. Another metabolite of fucoxanthin, amarouciaxanthin A, also showed a

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suppressive effect on 3T3-L1 adipocyte differentiation by decreasing the expression levels of transcription factors regulating adipocyte differentiation, e.g., PPAR and C/EBPα, and GPDH activity [80]. Furthermore, amarouciaxanthin A showed a stronger repressive effect on GPDH activity and the gene expression of fatty acid-binding protein 4, lipoprotein lipase, and glucose transporter 4 (GLUT4) than fucoxanthinol.

Anti-diabetic effect

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Journal Pre-proof Diabetes mellitus is a complex metabolic disturbance closely related to obesity, which is characterized by increased blood glucose, mainly due to insulin resistance caused by excessive lipid accumulation in obesity [81, 82]. According to the World Health Organization, diabetes was the 7th leading cause of death in 2016 with the estimated number of death of 1.6 million [83]. The incidence of diabetes mellitus was increased from 108 million in 1980 to 422 million in 2014 [83]. Diabetes mellitus may cause severe complications, such as kidney disease,

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blindness, heat attack, and stroke [84]. Therefore, it is vital to prevent or treat diabetes to avoid

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complications.

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Studies in mice have shown that fucoxanthin has an anti-diabetic effect by modulating

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the insulin signaling pathway. In obese/diabetic KK-Ay mice, daily 0.1% fucoxanthin consumption for 27 days significantly reduced plasma glucose levels and glucose intolerance

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with concomitant decreases in the expression of pro-inflammatory genes, such as TNFα and

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MCP-1, in white adipose tissue [85]. In the same mouse model, 0.2% fucoxanthin supplementation for 2 weeks decreased glucose and insulin levels in the circulation [86]. This

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anti-diabetic effect of fucoxanthin in KK-Ay mice was linked to enhanced GLUT4 translocation

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to the cell membrane in soleus and extensor digitorum longus muscles, indicating insulin sensitivity was induced by fucoxanthin in mice. Indeed, fucoxanthin increased the expression of insulin receptor and the phosphorylation of Akt in soleus and extensor digitorum longus muscles [86]. Furthermore, KK-Ay mice fed 0.2% fucoxanthin (w/w) daily for 4 weeks showed significant reductions in leptin and TNFα mRNA levels in white adipose tissue, which contributed to the improvement of insulin resistance and reduction of blood glucose levels [75]. In db/db mice, fucoxanthin supplementation at 0.2% and 0.4% by weight reduced fasting blood glucose levels, improved intraperitoneal glucose tolerance, and enhanced intraperitoneal insulin

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Journal Pre-proof tolerance [68]. The effect of fucoxanthin was mediated by insulin receptor substrate 1/ PI3K/Akt and AMPK signaling pathways in the liver and skeletal muscle. In a diet-induced obesity model, fucoxanthin markedly reduced the concentration of blood glucose and hemoglobin A1c levels with a concomitant decrease in plasma insulin and resistin concentrations [87]. Also, in high-fat diet-induced C57BL/6J mice, supplementation of fucoxanthin-rich wakame lipid extract markedly decreased plasma insulin and glucose levels concomitantly with an increase in GLUT4

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expression and β3-adrenergic receptor but a decrease in MCP-1 expression [88]. As such,

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mounting evidence supports that fucoxanthin attenuates high-fat diet-induced insulin resistance

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in mouse models of obesity and diabetes.

Hepatoprotective effect

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Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the

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U.S., is characterized by excess lipid accumulation, inflammation, and fibrosis in the liver without significant alcohol consumption [89, 90]. Simple steatosis, i.e., excess lipid

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accumulation mainly in hepatocytes, is considered as benign, while the advanced form of

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NAFLD such as nonalcoholic steatohepatitis has hepatocyte injury or cell death with inflammation and fibrosis in the liver [91]. It may further progress to cirrhosis with excess deposition of extracellular matrix. Studies have investigated the effect of fucoxanthin on the inhibition of hepatic lipid accumulation. In high-fat diet (20% fat, w/w)-fed C57BL/6J mice, the consumption of fucoxanthin at 0.05% or 0.2% level by weight for 6 weeks significantly reduced hepatic triglyceride and cholesterol accumulation [87]. This hepatoprotective effect of fucoxanthin was likely mediated by suppression of hepatic lipogenesis with increased hepatic lipolysis. The

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Journal Pre-proof activities of enzymes related to fatty acid synthesis, including FAS, G6PD, and ME, were significantly suppressed by fucoxanthin, while genes related to fatty acid β-oxidation, e.g., acylCoA oxidase1 and PPARα, were significantly induced by fucoxanthin in the liver [87]. Also, supplementation of fucoxanthin-rich extract of Undaria pinnatifida, an edible brown alga, significantly reduced hepatic lipid content in high-fat diet-induced obesity mice, which was attributed to reduced activities of enzymes involved in fatty acid synthesis, including FAS, ME,

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and G6PD, with a concomitant increase in fatty acid oxidation in the liver [92]. Also, the

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activities of enzymes for cholesterol metabolism, such as 3-hydroxy-3-methylglutaryl coenzyme

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A reductase and acyl-CoA cholesterol acyltransferase, were significantly decreased by the supplementation of fucoxanthin-rich seaweed extract [92].

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It has been shown that fucoxanthin can alter lipid composition in the liver. In KK-Ay mice,

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fucoxanthin downregulated the expression of hepatic stearoyl-coenzyme A desaturase-1 [93],

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which catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids and improves insulin sensitivity in diet-induced obesity mice [94]. Therefore, fucoxanthin feeding

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changed fatty acid composition such as stearic acid and oleic acid in the liver of KK-Ay mice,

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decreasing the ratios of oleic acid to stearic acid. Interestingly, oleic acid-induced hepatic lipid accumulation and lipid peroxidation were significantly attenuated by fucoxanthin in FL83B hepatocytes [95]. The inhibitory effect of fucoxanthin on lipid accumulation was attributed to the suppression of lipogenic genes, such as SREBP-1c, PPARγ and FAS, while increasing the expression of genes for lipolysis and β-oxidation, e.g., adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, CPT-1, CPT-2, and PPARα. The beneficial effect of fucoxanthin on the prevention of NAFLD may also be due to its anti-fibrogenic properties. The activation of hepatic stellate cells (HSCs) is an essential event in

17

Journal Pre-proof the development of liver fibrosis. Upon liver injury, quiescent HSCs are transdifferentiated into activated HSCs, which have high expression of fibrogenic genes including, α smooth muscle actin and procollagen type I a1 [96]. We recently demonstrated that fucoxanthin attenuated transforming growth factor β1 (TGFβ1)-induced pro-fibrogenic gene expression by the inhibition of SMA- and MAD-related protein activation in LX-2 cells as well as primary human HSCs [96]. Also, using primary mouse HSCs, we showed that fucoxanthin inhibited the transdifferentiation

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of quiescent HSCs to activated HSCs in the same study. Furthermore, fucoxanthin prevented

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TGFβ1-induced ROS accumulation, at least in part, by inhibiting the expression of NADPH

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oxidase 4, an enzyme that generates ROS, which is likely to contribute to the anti-fibrogenic

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effect of fucoxanthin.

Studies have shown a protective effect of fucoxanthin on oxidative stress in hepatic cell

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lines. Ferric nitrilotriacetate (Fe-NTA) treatment significantly reduced cell viability, while the

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presence of fucoxanthin significantly attenuated Fe-NTA-inhibited cell proliferation in hepatic BNL CL.2 cells [97]. This protective effect of fucoxanthin is likely attributed to decreased

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intracellular ROS, thiobarbituric acid reactive substances level, and protein carbonyl contents

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with increased glutathione levels [97]. Also in HepG2 cells, fucoxanthin prevented arachidonic acid+ iron-induced oxidative stress and increased expression of apoptosis-related proteins, mitochondrial dysfunction, and autophagy, which were attributed to the liver kinase B1-AMPKα signaling pathway [98].

Conclusion Fucoxanthin, a xanthophyll carotenoid, has a unique chemical structure that confers a strong antioxidant capacity by scavenging singlet molecular oxygen and free radicals. Studies

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Journal Pre-proof have demonstrated the potential health benefits of fucoxanthin, including anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, and hepatoprotective effects (Figure 3). Therefore, fucoxanthin has potential as a preventative/therapeutic agent for the diseases. However, although no toxic effect of fucoxanthin has been reported from animal studies, clinical trials to determine the safety of fucoxanthin consumption in humans are needed. Furthermore, as fucoxanthin can be metabolized to fucoxanthinol in the gastrointestinal tract and further to amarouciaxanthin A in

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the liver, in vitro studies using the fucoxanthin metabolites are necessary for the better

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mechanistic understanding of how fucoxanthin exerts its health benefits.

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Acknowledgments

This work was supported by USDA Multistate Hatch CONS00992 to J.-Y. Lee and

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USDA Hatch CONS00978 to Y.-K Park.

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[96] M.-B. Kim, M. Bae, S. Hu, H. Kang, Y.-K. Park, J.-Y. Lee, Fucoxanthin exerts antifibrogenic effects in hepatic stellate cells, Biochemical and biophysical research communications, (2019). [97] C.-L. Liu, A.-L. Liang, M.-L. Hu, Protective effects of fucoxanthin against ferric nitrilotriacetate-induced oxidative stress in murine hepatic BNL CL. 2 cells, Toxicology in Vitro, 25 (2011) 1314-1319. [98] E.J. Jang, S.C. Kim, J.-H. Lee, J.R. Lee, I.K. Kim, S.Y. Baek, Y.W. Kim, Fucoxanthin, the constituent of Laminaria japonica, triggers AMPK-mediated cytoprotection and autophagy in hepatocytes under oxidative stress, BMC complementary and alternative medicine, 18 (2018) 97.

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Journal Pre-proof Figure legends Figure 1. Structure of fucoxanthin.

Figure 2. Biotransformation of fucoxanthin. Fucoxanthin can be hydrolyzed to fucoxanthinol in the gastrointestinal tract and further converted into amarouciaxanthin A in the liver

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Figure 3. Health benefits of fucoxanthin and its metabolites. Fucoxanthin and its metabolites,

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fucoxanthinol and amarouciaxanthin A, exert anti-inflammatory, anti-cancer, anti-obesity, anti-

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diabetic, and hepatoprotective effects.

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Journal Pre-proof Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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Figure 1

Figure 2

Figure 3