Original articleOmega-3 fatty acid containing diets decrease plasma triglyceride concentrations in mice by reducing endogenous triglyceride synthesis and enhancing the blood clearance of triglyceride-rich particles
Introduction
Hypertriglyceridemia, the most common type of dyslipidemia, is a risk factor for progression of atherosclerosis and a strong independent predictor of future myocardial infarction.1, 2 Consumption of n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present in high amounts in some fish oil, reduce both fasting and postprandial triglyceride (TG) concentrations in humans as well as in experimental animals.2 n-3 fatty acids are used for treatment of patients with dyslipidemia. Recommendations from the American Heart Association include ingesting more fish oil n-3 fatty acids for patients with coronary heart diseases and hypertriglyceridemia.3, 4 However, the mechanisms of TG-reducing effects of n-3 fatty acids have not been fully determined and conflicting observations exist on some of these pathways.
There is a large body of evidence which shows that n-3 fatty acids reduce plasma TG concentrations through reduced endogenous very low density lipoprotein production.2, 5, 6, 7, 8 This does not preclude a contribution of enhanced TG-rich lipoprotein clearance, which may be mediated through altered particle size, structure or chemical composition9, 10 or altered lipoprotein lipase (LPL) activity and mass.2, 8 It has been suggested that n-3 fatty acids increase LPL or hepatic lipase (HL) activity,11, 12 but several investigators demonstrated that n-3 fatty acids do not affect or even decrease the enzymes' activity.13, 14, 15 Regarding the effects of n-3 fatty acids on TG-rich lipoprotein clearance, some researchers reported accelerated chylomicron TG clearance16, 17, 18 but no changes were found by others.5, 19, 20 In mouse models, we have reported faster clearance of n-3 TG enriched lipid emulsions as compared to n-6 rich emulsions.9, 10 The controversy in the mechanisms of TG-reducing effects of n-3 fatty acids may possibly be ascribed to differences in subjects (human vs. animals), content of n-3 fatty acids, TG composition in diets, duration of experiments, or other factors.
Human diets have changed greatly in the past 50–100 years, especially in the types of fat and fatty acids ingested.21 In modern society more saturated fat, n-6 fatty acids and trans fatty acids are being consumed with decreases in n-3 fatty acid intake: changes which may have contributed to increases in nutrition-related chronic diseases, including cardiovascular diseases, diabetes, obesity, cancer, immune-related diseases, and others. An appropriate ratio of n-3 to other fatty acids in diet is an important determinant of human health.21 To date, in most studies, the quantity of fish oil accounts for less than 10% of total fat intake; also only some of the potential metabolic effects of dietary n-3 fatty acids have been examined. In the present study, we utilized high-fat diets containing 15% of fat as fish oil and also pure fish oil to delineate their effects on TG metabolism, including LPL activities, hepatic TG synthesis and removal of exogenous chylomicron-like lipid emulsions using a mouse model.
Section snippets
Diets
Three dietary regimes with high-fat (18% fat wt/wt) – soy oil, fish oil and mixture of soy oil and fish oil (soy/fish) (5:1 wt/wt) and a control chow diet (6% fat from soy oil, wt/wt) were used. Each of the three high-fat diets was designed with the same baseline containing 230 g of casein, 180 g of corn starch, 150 g of maltodextrin, 150 g of sucrose, 40 g of mineral mix (AIN-93G-MX), 11 g of vitamin mix (AIN-93-VX), 47 g of cellulose, 4.6 g of calcium phosphate and 5.2 g of choline per kilogram. In
Effects of dietary fish oil on plasma TG levels
In both fed and fasted states, plasma TG levels in fish oil group (0.33 ± 0.06 and 0.23 ± 0.06 mmol/L) and soy/fish oil group (0.39 ± 0.05 and 0.19 ± 0.06 mmol/L) were both substantially lower than in soy oil group (0.68 ± 0.18 and 0.59 ± 0.17 mmol/L) (P < 0.001), and were very similar to the control group on a normal chow diet (0.40 ± 0.05 mmol/L and 0.20 ± 0.05 mmol/L) (P > 0.05) (Fig. 1).
Effects of dietary fish oil on activities of LPL in plasma
LPL, the key enzyme in TG lipolysis, plays an important role in maintaining blood TG concentration. Thus, we analyzed the LPL
Discussion
Fish oil enriched with n-3 fatty acids exerts beneficial effects on human health, including plasma TG-lowering.2, 3, 4, 24 In this study, using mouse models fed high-fat diets with different fatty acid compositions, we found that diets containing pure fish oil or 15% of fish oil in terms of total fat significantly reduced plasma TG concentrations by 40–60% both in fasting and postprandial states.
The hypotriglyceridemic action of n-3 fatty acids has been attributed to their inhibition on
Conflict of interest statement
There are no financial conflicts of interest for all authors.
Acknowledgements
This work was supported by National Natural Science Foundation of China (NSFC) (30200303) (K.Q.) and the Scientific Research Foundation for the Returned Oversees Chinese Scholars, State Education Ministry (2002) (K.Q.), and by NIH grant HL40404 (R.J.D.).
References (34)
- et al.
Effects of long-chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism
Am J Clin Nutr
(2000) - et al.
Reduced hepatic triglyceride secretion in rats fed docosahexaenoic acid-rich fish oil suppresses postprandial hypertriglyceridemia
J Nutr
(2001) - et al.
Triglycerides in fish oil affect the blood clearance of lipid emulsions containing long- and medium-chain triglycerides in mice
J Nutr
(2006) - et al.
Influence of n-3 fatty acid supplementation on the endogenous activities of plasma lipases
Am J Clin Nutr
(1997) - et al.
Dietary long-chain n-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype
J Lipid Res
(2002) - et al.
Postheparin lipolytic activity and plasma lipoprotein response to omega-3 polyunsaturated fatty acids in patients with primary hypertriglyceridemia
Am J Clin Nutr
(1991) - et al.
Lipoprotein lipase, lipoproteins and tissue lipids in rats fed fish oil or coconut oil
J Nutr
(1987) - et al.
Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance
J Lipid Res
(2003) - et al.
Postprandial chylomicrons and VLDLs in severe hypertriacylglycerolemia are lowered more effectively than are chylomicron remnants after treatment with n-3 fatty acids
Am J Clin Nutr
(2000) - et al.
n-3 fatty acids and chylomicron metabolism in the rats
J Lipid Res
(1997)
Fish oil reduces postprandial triglyceride concentrations without accelerating lipid emulsion removal rates
Am J Clin Nutr
Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity
Am J Clin Nutr
Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases
Biomed Pharmacother
Lipoprotein lipase: genetics, lipid uptake, and regulation
J Lipid Res
Triacylglycerol-rich lipoprotein margination: a potential surrogate for whole-body lipoprotein lipase activity and effects of eicosapentaenoic and docosahexaenoic acids
Am J Clin Nutr
Fish oil feeding decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-1c mRNA in mouse liver. A possible mechanism for down-regulation of lipogenic enzyme mrnas
J Biol Chem
Increased dietary triacylglycerol markedly enhances the ability of isolated rabbit enterocytes to secrete chylomicrons: an effect related to dietary fatty acid composition
J Lipid Res
Cited by (59)
The docosahexaenoic acid derivatives, diHEP-DPA and TH-DPA, synthesized via recombinant lipoxygenase, ameliorate disturbances in lipid metabolism and liver inflammation in high fat diet-fed mice
2022, Life SciencesCitation Excerpt :As shown in Fig. 4C and D, adiponectin concentrations were significantly reduced in the HFD-only group (1890.67 ± 83.68 ng/mL), an effect that was abrogated by treatment with diHEP-DPA (2744.33 ± 127.19 ng/mL) or TH-DPA (2485.67 ± 106.55 ng/mL); conversely, leptin concentrations were significantly increased in the HFD-only group (4367.33 ± 50.64 ng/mL), and treatment with diHEP-DPA (3725.67 ± 222.80 ng/mL) and TH-DPA (3386.67 ± 143.51 ng/mL) reversed this effect. The adiponectin/leptin ratio has been proposed as a marker of adipose tissue dysfunction [21,22]. Based on previous data, we considered adiponectin/leptin ratios ≥1.0 (where adiponectin concentrations are expressed as ng/mL and leptin levels as pg/mL) as normal, ratios between 0.5 and 1.0 as medium-moderately increased risk, and ratios <0.5 as suggesting a severe increase in cardiometabolic risk [22].
Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases
2017, Drug Discovery TodayFatty acids and cardiac ischemia reperfusion injury
2016, Handbook of Lipids in Human Function: Fatty Acids