Hypercholesteremia results in cognitive decline, while higher intakes of marine n-3 polyunsaturated fatty acids (PUFA) can ameliorate mild cognitive impairment (MCI). However, whether individual n-3 PUFA, notably docosahexaenoic acid (DHA, C_22:6n-3) and eicosapentaenoic acid (EPA, C_20:5n-3) have different efficiency to ameliorate MCI remain ambiguous. This study aimed to investigate the underlying mechanism why DHA had superior functions to ameliorate MCI. Here, a case-control study with 1:2 case-to-control ratio was implemented. It showed that serum ceramide concentrations were significantly higher in MCI patients compared with healthy controls, and were negatively associated with DHA composition in erythrocyte phospholipids. The MCI model was established with male C57BL/6J wild-type mice fed a high-fat and high-cholesterol diet (HFD), and administration of DHA led to ameliorated cognitive behavior abnormalities and neuronal apoptosis. The improvement of MCI phenotype was further recapitulated in low-density lipoprotein receptor knockout (LDLR^−/−) mice treated with DHA. Mechanistically, DHA could remodel composition of phospholipid membranes, leading to reduced endocannabinoid ligands and inhibited cannabinoid receptor 1 (CB1). The restrained endocannabinoid system was bound up with inhibited ceramide-induced apoptosis of neurons. This work reveals a novel mechanism, namely CB1-ceramide axis, through which DHA exhibits an alleviation in HFD-induced MCI.

Metabolic dysfunction-associated fatty liver disease (MAFLD), characterized as hepatic triglyceride accumulation, affects a quarter of the adult population worldwide, but limited therapeutic approaches are available in the treatment of MAFLD. It is widely believed that marine n-3 polyunsaturated fatty acids (PUFA) intervention could ameliorate MAFLD, however, the underlying mechanism remains elusive. Herein, in a case-control study, we identified serum C16:0-ceramide as a biomarker indicating MAFLD patients, which was negatively associated with n-3 PUFA levels in red blood cell phospholipids. The causality was confirmed by a randomized controlled trial (RCT), highlighting that supplemental n-3 PUFA had notable action in lowering serum C16:0-ceramide concentrations. The RCT indicated that serum adiponectin levels were negatively associated with serum C16:0-ceramide levels. An MAFLD model was established in mice fed a high-fat, high-cholesterol diet, and administration of n-3 PUFA increased adiponectin secretion and decreased hepatic C16:0-ceramide concentrations associated with reduced hepatic steatosis. In these mice, adiponectin administration contributed to decreased hepatic C16:0-ceramide concentrations and alleviated hepatic triglyceride accumulation through reduced de novo fatty acid synthesis and increased fatty acid β-oxidation. Furthermore, administration of C16:0-ceramide reversed the beneficial effects of n-3 PUFA in high-fat diet-induced MAFLD. This work reveals a novel mechanism, namely adiponectin-C16:0-ceramide axis, through which n-3 PUFA play a notable role in ameliorating MAFLD.

Whether different forms of n-3 polyunsaturated fatty acids (PUFA) have differential functions to improve cardiac damage remain elusive. The present study aimed to investigate different forms of n-3 PUFA intervention, namely eicosapentaenoic acid (C20:5n-3, EPA)/docosahexaenoic acid (C22:6n-3, DHA)-triglyceride (TAG), DHA/EPA-phospholipid (PL), and krill oil on high-fat/high-cholesterol diet (HFD)-induced myocardial injury. After 18 weeks of HFD feeding, the mice exhibited myocardial hypertrophy and disordered arrangement of cardiomyocytes. However, administration of the three forms of n-3 PUFA significantly led to alleviated myocardial hypertrophy and arrangement of myocardial cells in the C57BL/6J mice under HFD challenge. Meanwhile, administration of the three forms of n-3 PUFA ameliorated myocardial hypertrophy in low-density lipoprotein receptor knockout (LDLR-/-) mice. However, n-3 PUFA intervention ameliorated HFD-induced cardiac dysfunction by increasing ejection fraction and fraction shortening levels, no significant difference was observed with respect to cardiac dysfunction between the three forms of n-3 PUFA groups. The lipidomics and targeted lipidomics analyses identified and confirmed that cardiac C18:0-, C20:0-, C22:0-, and total ceramide concentrations in EPA/DHA-TAG and DHA/EPA-PL groups were significantly lower in comparison with the HFD group. Mechanistically, n-3 PUFA treatment significantly increased the protein expression levels of adiponectin and acid ceramidase, which accelerate ceramide catabolism. The reduced cardiac ceramide concentrations were associated with remodeling mitochondrial dynamics homeostasis and decreased dynamin-related protein 1 (Drp1) and mitochondrial fission factor (MFF) levels. Consequently, the protein expression levels of caspase 3 and recombinant tumor protein p53 (p53) were significantly decreased in the three n-3 PUFA groups compared with the HFD group. This work reveals that n-3 PUFA mitigate cardiac dysfunction through the adiponectin/ceramide/apoptosis axis, but there is no significant difference between the three forms of n-3 PUFA groups.

The associations of individual amino acid with non-alcoholic fatty liver disease (NAFLD) risk remained unclear. The present study aimed to investigate the associations between the two in the Chinese elderly. Methods: A community-based health check-up program was conducted in Qingdao, China. NAFLD was diagnosed by ultrasonography accompanied by epidemiological investigation. The dietary intakes of amino acids were investigated with 3-day, 24-h dietary records and calculated by Nutrition Calculator software. Restricted cubic spline model was used to evaluate a nonlinear relationship between amino acid intake and NAFLD risk. Results: 400 NAFLD subjects were identified, and 400 participants were randomly selected as controls and matched by gender and age (± 3 years) Dose-response analysis showed that 1000 mg increment of aromatic amino acids (AAAs) was associated with reduced 16% risk of NAFLD. Dietary increments of 750 mg/d threonine, 950 mg/d valine, or 1700 mg/d lysine were associated with a 20% reduction in the NAFLD risk (all P for linearity < 0.05). Conclusion: The present study demonstrated that the dietary increases in milk, eggs and deep-sea fish, which are rich in the amino acids, might contribute to protecting against NAFLD in the elderly.