Docosahexaenoic Acid-Acylated Astaxanthin Monoester Ameliorates Amyloid-ß Pathology and Neuronal Damage by Restoring Autophagy in Alzheimer's Disease Models.

SCOPE: Astaxanthin (AST) is ubiquitous in aquatic foods and microorganisms. The study previously finds that docosahexaenoic acid-acylated AST monoester (AST-DHA) improves cognitive function in Alzheimer's disease (AD), although the underlying mechanism remains unclear. Moreover, autophagy is reportedly involved in amyloid-ß (Aß) clearance and AD pathogenesis. Therefore, this study aims to evaluate the preventive effect of AST-DHA and elucidates the mechanism of autophagy modulation in Aß pathology. METHODS AND RESULTS: In the cellular AD model, AST-DHA significantly reduces toxic Aß1-42 levels and alleviated the accumulation of autophagic markers (LC3II/I and p62) in Aß25-35 -induced SH-SY5Y cells. Notably, AST-DHA restores the autophagic flux in SH-SY5YmRFP-GFP-LC3 cells. In APP/PS1 mice, a 3-month dietary supplementation of AST-DHA exceeded free-astaxanthin (F-AST) capacity to increase hippocampal and cortical autophagy. Mechanistically, AST-DHA restores autophagy by activating the ULK1 signaling pathway and restoring autophagy-lysosome fusion. Moreover, AST-DHA relieves ROS production and mitochondrial stress affecting autophagy in AD. As a favorable outcome of restored autophagy, AST-DHA mitigates cerebral Aß and p-Tau deposition, ultimately improving neuronal function. CONCLUSION: The findings demonstrate that AST-DHA can rectify autophagic impairment in AD, and confer neuroprotection in Aß-related pathology, which supports the future application of AST as an autophagic inducer for maintaining brain health.

Dietary Eicosapentaenoic Acid Containing Phosphoethanolamine Plasmalogens Remodels the Lipidome of White Adipose Tissue and Suppresses High-Fat Diet Induced Obesity in Mice.

SCOPE: Dietary supplementation of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) can alter the lipidome profiles of adipocytes, thereby counteract obesity. DHA/EPA in the form of phospholipids demonstrates higher bioavailability than triglyceride or ethyl ester (EE), but their effects on the lipidome and metabolic changes during obesity are still unknown. METHODS AND RESULTS: High-fat diet-induced obese mice are treated with different molecular forms of EPA, and EPA supplemented as phosphoethanolamine plasmalogens (PlsEtn) has a superior effect on reducing fat mass accumulation than phosphatidylcholine (PC) or EE. The lipidomics analysis indicates that EPA in form of PlsEtn but not PC or EE significantly decreases total PC and sphingomyelin content in white adipose tissue (WAT). Some specific polyunsaturated fatty acid -containing PCs and ether phospholipids are increased in EPA-PlsEtn-fed mice, which may attribute to the upregulation of unsaturated fatty acid biosynthesis and fatty acid elongation reactions in WAT. In addition, the expression of genes related to fatty acid catabolism is also promoted by EPA-PlsEtn supplementation, which may cause the decreased content of saturated and monounsaturated fatty acid-containing PCs. CONCLUSIONS: EPA-PlsEtn supplementation is demonstrated to remodel lipidome and regulate the fatty acid metabolic process in WAT, indicating it may serve as a new strategy for obesity treatment in the future.

Liver Lipidomics Analysis Revealed the Novel Ameliorative Mechanisms of L-Carnitine on High-Fat Diet-Induced NAFLD Mice.

The beneficial effects of L-carnitine on non-alcoholic fatty liver disease (NAFLD) were revealed in previous reports. However, the underlying mechanisms remain unclear. In this study, we established a high fat diet (HFD)-induced NAFLD mice model and systematically explored the effects and mechanisms of dietary L-carnitine supplementation (0.2% to 4%) on NAFLD. A lipidomics approach was conducted to identify specific lipid species involved in the ameliorative roles of L-carnitine in NAFLD. Compared with a normal control group, the body weight, liver weight, concentrations of TG in the liver and serum AST and ALT levels were dramatically increased by HFD feeding (p < 0.05), accompanied with obvious liver damage and the activation of the hepatic TLR4/NF-κB/NLRP3 inflammatory pathway. L-carnitine treatment significantly improved these phenomena and exhibited a clear dose-response relationship. The results of a liver lipidomics analysis showed that a total of 12 classes and 145 lipid species were identified in the livers. Serious disorders in lipid profiles were noticed in the livers of the HFD-fed mice, such as an increased relative abundance of TG and a decreased relative abundance of PC, PE, PI, LPC, LPE, Cer and SM (p < 0.05). The relative contents of PC and PI were significantly increased and that of DG were decreased after the 4% L-carnitine intervention (p < 0.05). Moreover, we identified 47 important differential lipid species that notably separated the experimental groups based on VIP ≥ 1 and p < 0.05. The results of a pathway analysis showed that L-carnitine inhibited the glycerolipid metabolism pathway and activated the pathways of alpha-linolenic acid metabolism, glycerophospholipid metabolism, sphingolipid metabolism and Glycosylphosphatidylinositol (GPI)-anchor biosynthesis. This study provides novel insights into the mechanisms of L-carnitine in attenuating NAFLD.

Docosahexaenoic acid-acylated astaxanthin monoester ameliorates chronic high-fat diet-induced autophagy dysfunction via ULK1 pathway in the hypothalamus of mice.

BACKGROUND: Dietary astaxanthin (AST) exhibits the ability to resist lipid accumulation and stimulate hepatic autophagy. Natural AST predominantly exists in stable esterified forms. More importantly, in our previous study, docosahexaenoic acid-acylated AST monoester (AST-DHA) possessed better stability, bioavailability, and neuroprotective ability than AST in free and diester form. However, the AST-DHA mechanisms of action in regulating the obese phenotype and autophagy of the central nervous system remain unclear. RESULTS: High-fat diet (HFD)-fed C57BL/6J mice were orally administered AST-DHA (50 mg/kg body weight/d) for 3 days or 8 weeks. AST-DHA supplementation alleviated HFD-induced abnormal body weight gain, significantly enhanced autophagy with an increased microtubule-associated protein light chain 3 II/I (LC3II/I) ratio, and reduced the accumulation of p62/sequestosome 1 (SQSTM1) in the hypothalamus rather than in the hippocampus. Mechanistically, AST-DHA effectively promoted autophagy and autophagosome formation, and most notably rescued the HFD-impaired autophagosome-lysosome fusion (indicated by the colocalization of LC3 and LAMP1) by regulating mTOR- and AMPK-induced phosphorylation of ULK1. Consequently, AST-DHA enhanced hypothalamic autophagy, leading to pro-opiomelanocortin (POMC) cleavage to produce alpha-melanocyte-stimulating hormone (α-MSH). CONCLUSIONS: This study identified AST-DHA as an enhancer of autophagy that plays a beneficial role in restoring hypothalamic autophagy, and as a new potential therapeutic agent against HFD-induced obesity. © 2023 Society of Chemical Industry.

Hepatoprotective effects of sea cucumber ether-phospholipids against alcohol-induced lipid metabolic dysregulation and oxidative stress in mice.

Sea cucumber is widely consumed as food and folk medicine in Asia, and its phospholipids are rich sources of dietary eicosapentaenoic acid enriched ether-phospholipids (ether-PLs). Emerging evidence suggests that ether-PLs are associated with neurodegenerative disease and steatohepatitis. However, the function and mechanism of ether-PLs in alcoholic liver disease (ALD) are not well understood. To this end, the present study sought to investigate the hepatoprotective effects of sea cucumber ether-PLs, including plasmenyl phosphatidylethanolamine (PlsEtn) and plasmanyl phosphatidylcholine (PlsCho), and their underlying mechanisms. Our results showed that compared with EtOH-induced mice, ether-PL treated mice showed improved liver histology, decreased serum ALT and AST levels, and reduced alcohol metabolic enzyme (ALDH2 and ADH1) expressions. Mechanistic studies showed that ether-PLs attenuated "first-hit" hepatic steatosis and lipid accumulation evoked by alcohol administration. Moreover, PlsEtn more effectively restored endogenous plasmalogen levels than PlsCho, thereby enhancing hepatic antioxidation against "second-hit" reactive oxygen species (ROS) due to the damaged mitochondria and abnormal ethanol metabolism. Taken together, sea cucumber ether-PLs show great potential to become a natural functional food against chronic alcohol-induced hepatic steatosis and lipid metabolic dysregulation.

Lipidomics Approach in High-Fat-Diet-Induced Atherosclerosis Dyslipidemia Hamsters: Alleviation Using Ether-Phospholipids in Sea Urchin.

Ether-phospholipids (ether-PLs) in sea urchins, especially eicosapentaenoic-acid-enriched plasmenyl phosphatidylethanolamine (PE-P) and plasmanyl phosphatidylcholine (PC-O), exhibit potential lipid-regulating effects. However, their underlying regulatory mechanisms have not yet been elucidated. Herein, we integrated an untargeted lipidomics strategy and biochemical analysis to investigate these mechanisms in high-fat-induced atherosclerotic hamsters. Dietary supplementation with PE-P and PC-O decreased total cholesterol and low-density lipoprotein cholesterol concentrations in serum. The lipid regulatory effects of PE-P were superior to those of PC-O. Additionally, 20 lipid molecular species, including phosphatidylethanolamine, cholesteryl ester, triacylglycerol, and phosphatidylinositol, were identified as potential lipid biomarkers in the serum of hamsters with PC-O and PE-P treatment (95% confidence interval; p < 0.05). The variations of lipids may be attributed to downregulation of adipogenesis genes and upregulation of lipid ß-oxidation genes and bile acid biosynthesis genes. The improved lipid homeostasis by ether-PLs in sea urchins might be a key pathway underlying the antiatherosclerosis effect.

Effects of Dietary Supplementation with EPA-enriched Phosphatidylcholine and Phosphatidylethanolamine on Glycerophospholipid Profile in Cerebral Cortex of SAMP8 Mice fed with High-fat Diet.

The destruction of lipid homeostasis is associated with nervous system diseases such as Alzheimer's disease (AD). It has been reported that dietary EPA-enriched phosphatidylcholine (EPA-PC) and phosphatidylethanolamine (EPA-PE) could improve brain function. However, it was unclear that whether EPA-PC and EPA-PE intervention could change the lipid composition of cerebral cortex in AD mice. All the senescence-accelerated mouse-prone 8 (SAMP8) mice were fed with a high-fat diet for 8 weeks. After another 8 weeks of intervention with EPA-PC and EPA-PE (1%, w/w), the cerebral cortex lipid levels were determined by lipidomics. Results demonstrated that dietary supplementation with EPA-PE and EPA PC for 8 weeks significantly increased the amount of choline plasmalogen (pPC) and Lyso phosphatidylethanolamine (LPE) in the cerebral cortex of SAMP8 mice fed with high fat diet. Meanwhile, administration with EPA-PE and EPA-PC could significantly decrease the level of docosapentaenoic acid (DPA)-containing phosphatidylserine (PS) as well as increase the levels of arachidonic acid (AA)-containing phosphatidylethanolamine and PS in cerebral cortex. EPA-PE and EPA-PC could restore the lipid homeostasis of dementia mice to a certain degree, which might provide a potential novel therapy strategy and direction of dietary intervention in patients with cognitive impairment.

Recovery of brain DHA-containing phosphatidylserine and ethanolamine plasmalogen after dietary DHA-enriched phosphatidylcholine and phosphatidylserine in SAMP8 mice fed with high-fat diet.

BACKGROUND: Glycerophospholipids were the main components of cerebral cortex lipids, and there was a close association between lipid homeostasis and human health. It has been reported that dietary DHA-enriched phosphatidylcholine (DHA-PC) and phosphatidylserine (DHA-PS) could improve brain function. However, it was unclear that whether supplementation of DHA-PC and DHA-PS could change lipid profiles in the brain of dementia animals. METHODS: SAMP8 mice was fed with different diet patterns for 2 months, including high-fat diet and low-fat diet. After intervention with DHA-PC and DHA-PS for another 2 months, the lipid profile in cerebral cortex was determined by lipidomics in dementia mice. RESULTS: High-fat diet could significantly decrease the levels of DHA-containing PS/pPE, DPA-containing PS, and AA-containing PE, which might exhibit the potential of lipid biomarkers for the prevention and diagnosis of AD. Notably, DHA-PC and DHA-PS remarkably recovered the lipid homeostasis in dementia mice. These might provide a potential novel therapy strategy and direction of dietary intervention for patients with cognitive decline. CONCLUSIONS: DHA-PC and DHA-PS could recover the content of brain DHA-containing PS and pPE in SAMP8 mice fed with high-fat diet.

A comparative study of eicosapentaenoic acid enriched phosphatidylcholine and ethyl ester in improving cognitive deficiency in Alzheimer's disease model rats.

Abundant studies have highlighted the protective effects of docosahexaenoic acid (DHA), in the form of glycerolipids (glycerophosphatides and triglycerides) and DHA-ethyl esters (DHA-EE) in Alzheimer's disease (AD); however, eicosapentaenoic acid (EPA) has rarely been implicated. In the present study, we compared the effects of dietary EPA in the form of phosphatidylcholine (EPA-PC) and EE with DHA-EE (DHA/EPA = 60 mg kg-1 d-1, i.g., 20 days) on cognitive deficits in AD rats. EPA-PC, rather than EPA-EE, significantly improved Aß-induced cognitive impairment and has a comparable effect with DHA-EE. Further research indicated that EPA-PC and DHA-EE could significantly decrease lipid peroxidation levels, alleviate mitochondria-dependent apoptosis, and inhibit the hyperphosphorylation of tau mediated by GSK3ß. These findings suggest that EPA in the form of phosphatidylcholine rather than an ethyl ester has a comparable effect with DHA in improving cognitive impairment in Aß1-42-induced AD rats.

Cerebrosides from Sea Cucumber Protect Against Oxidative Stress in SAMP8 Mice and PC12 Cells.

Alzheimer's disease (AD) is a neurodegenerative disorder. Emerging evidence implicates ß-amyloid (Aß) plays a critical role in the progression of AD. In this study, we investigated the protective effect of cerebrosides obtained from sea cucumber against senescence-accelerated mouse prone 8 (SAMP8) mice in vivo. We also studied the effect of cerebrosides on Aß-induced cytotoxicity on the rat pheochromocytoma cell (PC12) and the underlying molecular mechanisms. Cerebrosides ameliorated learning and memory deficits and the Aß accumulation in demented mice, decreased the content of malondialdehyde (MDA), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG), 8-hydroxy-2'-deoxyguanosine (8-oxo-G), and nitric oxide (NO), and enhanced the superoxide dismutase (SOD) activity significantly. The neuroprotective effect of sea cucumber cerebrosides (SCC) was also verified in vitro: the cerebrosides increased the survival rate of PC12 cells, recovered the cellular morphology, downregulated the protein levels of Caspase-9, cleaved Caspase-3, total Caspase-3, and Bax, and upregulated the protein level of Bcl-2, revealing that cerebrosides could inhibit Aß-induced cell apoptosis. The results showed the protective effect of SCC was regulated by the mitochondria-dependent apoptotic pathway. Our results provide a new approach to developing the marine organisms as functional foods for neuroprotection.

Effects of dietary glucocerebrosides from sea cucumber on the brain sphingolipid profiles of mouse models of Alzheimer's disease.

Herein, we investigated the potential relationship between sphingolipids and Alzheimer's disease (AD) with special attention to the relationship between dietary sea cucumber glucocerebrosides (SCGs) and sphingolipid metabolism. We assessed animal behavior using the Morris water maze test, determined Aß1-42 concentration in the hippocampus using ELISA, and assessed the sphingolipid profile of the hippocampus and the cortex in normal mice (SAMR1), AD mice (SAMP8), and AD mice (SAMP8) fed with SCG using liquid chromatography-triple quadrupole mass spectrometry. We found that the SAMP8 mice had impaired memory and an SCG diet significantly rescued spatial memory deficits in these mice. As expected, we found that the profiles of sphingolipid species and the levels of total cerebrosides (CBS), ceramides (Cer), and sulfatides (ST) were significantly different in both the hippocampus and the cortex between the three groups; moreover, there were significantly lower ST levels and higher Cer and CBS levels in these regions in the SAMP8 mice. In the AD-SCG group, Cer and ST levels were altered only in the hippocampus, in contrast to the AD group. The major molecular species ST (d18:1-C24:1) and Cer (d18:1/18:0) were especially different between those of the two groups. Unexpectedly, sphingolipid profiles, including the nonhydroxylated fatty acid-ST/hydroxylated fatty acid-ST, very long fatty acid-galactocerebroside/long fatty acid-galactocerebroside, nonhydroxylated fatty acid-galactocerebroside/hydroxylated fatty acid-galactocerebroside and galactocerebroside/glucocerebroside ratios, were affected by AD. Thus, the ST and Cer levels and the profiles of sphingolipid species in the AD-SCG group were significantly different compared to those of the AD model group. Therefore, SCG has potential ameliorative effects in AD, and exogenous sphingolipid intake may potentially influence sphingolipid metabolism in vivo.