Clinical Lipidology

Clinical Lipidology

Editorial For reprint orders, please contact: [email protected]

Krill oil: evidence of a new source of polyunsaturated fatty acids with high bioavailability “Preliminary clinical trials suggest that Krill oil is an alternative source of polyunsaturated fatty acids with peculiar effects in humans.” Keywords: brain function • DHA • EPA • fatty acids • fish oil • hyperlipidemia • inflammation • Krill oil • non-alcoholic fatty liver disease • omega 3 • omega 6

Polyunsaturated essential fatty acids (PUFAs), and in particular omega 3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have several metabolic and pharmacological effects potentially useful in the management of a large number of human chronic diseases [1,2] . Given this potential role in therapy, the finding for new sources of omega 3 PUFAs is always a matter of interest [3] . A rich source of omega 3 PUFAs is the krill (Euphausia superba), a small crustacean that lives in the Antarctic Ocean, containing many types of long-chain PUFAs. Krill and fish oil differ in their composition: krill oil is comprised of phospholipids (for the 30–65%) and triglycerides, while fish oil is comprised of only triglycerides. The primary phospholipid in krill oil is phosphatidylcholine, with 40% of the total fatty acids attached to the PC being EPA and DHA [4] . This composition promotes the efficiency of absorption of fatty acids into the blood, justifying the high bioavailability of omega 3 PUFA assumed in this form. Krill oil also contains various potent antioxidants, including vitamins A and E, and astaxanthin, whose capacity of absorption of oxygen radicals proved to be 34-times higher than the one of Coenzyme Q10 and 48-times than the one of fish oil [5] .

the primarily responsible for its metabolic effects. Pedersen et al. randomized 130 subjects with normal or slightly elevated total blood cholesterol and/or triglyceride levels into three groups, taking either six capsules of Krill oil (3 g/die, EPA + DHA= 543 mg), three capsules of fish oil (1.8 g/die, EPA + DHA= 864 mg) or any supplementation for 7 weeks, concluding that lower doses of Krill oil have similar metabolic effect to the higher doses of fish oil [6] . Deutsch et al. enrolled 60 hypercholesterolemic patients and gave them Krill oil at a body mass index-dependent daily dosage of 1–3 g daily for 12 weeks; the results were compared with the ones of 30 patients receiving fish oil (540 mg EPA and 360 mg DHA daily) and of 30 patients receiving placebo. Krill oil achieved a significant reduction in baseline total cholesterol levels of 18%, an HDL cholesterol increase of 60% and a triglycerides reduction of of 27%, while fish oil at higher dosages only exerted a similar effect on triglycerides. Moreover, a maintenance dose of 500 mg Krill oil is significantly effective for long-term regulation of blood lipid levels [7] . Otherwise, the effect seems to be partly reduced in expressly obese subjects [8] .

Arrigo FG Cicero Author for correspondence: Medical & Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Italy Tel.: +39 0516362224 Fax: +39 516826125 arrigo.cicero@ unibo.it

Alessandro Colletti Medical & Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Italy

Inflammation

Krill oil: therapeutic uses tested in clinical trials Lipid profile

Preliminary clinical trials suggest that Krill oil is an alternative source of polyunsaturated fatty acids with peculiar effects in humans [6–16] . The highly bioavailable omega 3 PUFAs contained in Krill oil seems to be

10.2217/CLP.14.67 © 2015 Future Medicine Ltd

In a randomized double-blind study in patients with cardiovascular disease and/or rheumatoid arthritis and/or osteoarthritis and C reactive protein (CRP) >1 mg/dl treated with Krill oil 300 mg/day, after a short duration of treatment (7–14 days) a significant decrease in CRP (-31%) and in the WOMAC pain score (-28.9%), rigidity score

Clin. Lipidol. (2015) 10(1), 1–4

part of

ISSN 1758-4299

1

Editorial Cicero & Colletti (-20.3%) and functionality reduction score (-22.8%) was observed [9] . These interesting data have to be confirmed in a longer trial. The endocannabinoid system is also deeply involved in systemic inflammation and in the regulation of the homeostasis of body composition by regulating food intake and energy expenditure and [10] an overactive endocannabinoid system has been suggested to contribute to increased fat mass and to several features of metabolic syndrome. In fact, an increase of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in overweight and obese subjects has been described [11–13] .

“With the intake of krill oil, patients reported

a significant decrease in menstrual pain, a reduction in the consumption of analgesics (ibuprofen and acetaminophen reduced by more than 50%), with no reported side effects.

”

Griinari et al. conducted a trial on 63 healthy subjects, with waist circumference of 102 cm or greater (men) or 88 cm or greater (women), randomly assigned to one of three groups: 2 g/die of either Krill oil (providing 216 mg/d EPA and 90 mg/day DHA), Menhaden oil (providing 212 mg/day EPA and 178 mg/day DHA) or olive oil (control). Subjects were instructed to consume four 500 mg capsules per day for 4 weeks. Krill oil, but not Menhaden oil or Olive oil, was able to significantly decrease 2-AG, although only in obese subjects. In addition, the decrease of 2-AG was correlated to the plasma n-6/n-3 long-chain PUFA ratio improvement [14] . Premenstrual syndrome

Menstrual pain and cramps are mainly caused by inflammation mediated by omega 6 fatty acid-derived eicosanoids. Supplementation with omega 3 fatty acids mediates the production of less potent prostaglandings and leukotriens, resulting in a reduction in the severity of myometrial contractions and uterine vasoconstriction, a decrease in the formation of inflammatory mediators, and subsequently reduced ischemia and improved blood flow. A double-blind randomized clinical trial was conducted in 70 patients with premenstrual syndrome and dysmenorrhea to evaluate the effects of Krill oil as adjuvants in the treatment of these diseases, when compared with purified omega 3 PUFAs. During the first month, patients took 2 g of purified omega 3 PUFAs or 2 g of Krill oil daily. During the following 2 months, patients continued on a cyclic 1 g dose of two soft gels 8 days prior to, and 2 days during, menstruation. With the intake of Krill oil, patients reported a significant decrease in menstrual pain, a reduction in the consumption of analgesics

2

Clin. Lipidol. (2015) 10(1)

(ibuprofen and acetaminophen reduced by more than 50%), with no reported side effects. Moreover, the Krill oil was more effective than purified omega 3 PUFAs in the reduction of some types of menstrual pain including the joint pain, and breast tenderness. The psychophysical state of the subjects taking Krill oil was better than the equivalent group omega 3 PUFAs, as well [15] . Memory & cognitive function

Omega-3 PUFAs enhance and improve learning capability as well as memory and cognitive function even in the elderly. Koga et al. demonstrated that longterm ingestion of Krill oil promotes working memory function by activating the dorsolateral prefrontal cortex and prevent deterioration in cognitive activity. Continuous ingestion of Krill oil has been shown to expedite the information-processing rate. The study involved 45 healthy elderly males, which were assigned to receive 12 weeks of treatment with: medium-chain triglycerides as placebo; Krill oil (2 g/die), which is rich in omega-3 PUFAs incorporated in phosphatidylcholine; or sardine oil, which is abundant in omega-3 PUFAs incorporated in triglycerides. Changes in oxyhemoglobin concentrations in the cerebral cortex during memory and calculation tasks were measured. During the calculation tasks, the group of people of the study that received Krill oil showed significantly greater changes in oxyhemoglobin concentrations in the left frontal area (as compared with changes seen in the mediumchain triglyceride group). These results suggest that intake of Krill oil enhances the function of the cerebral hemisphere relating to calculation. Physiological measurement by near-infrared spectroscopy and EEG analyses demonstrated also that Krill oil has the effect of activating the function of the cerebral cortex [16] . In addition, preliminary data suggest that Krill oil could influence early brain development and mental performance, improving cognition, behavior and mood [17] . Venous leg ulcers

Topical application of Krill oil was also compared with a nonenzyme for the treatment of venous leg ulcers. A computerized evaluation of the photos of the lesions showed how Krill oil was able to reduce by 53% the necrotic area in 7 days, while no effect was observed for the control [18] . These data also require further confirmation. Conclusion Preliminary clinical data suggest that Krill oil could be an excellent aid in the treatment of various diseases including dyslipidemia, nonalcoholic fatty liver

future science group

Krill oil: evidence of a new source of polyunsaturated fatty acids with high bioavailability

disease, premenstrual syndrome and dysmenorrhea. It could be also useful in the prevention of certain diseases such as Alzheimer disease, in the protection of brain function and protection against inflammation. Owing to its composition, it has a higher bioavailability than fish oil, resulting in the same efficacy and effects similar to fish oil, but with lower doses. This could also have a positive impact on fish source wasting. Currently, toxicity levels for Krill oil are not known. Side effects are minimal or absent; in the latter case may include flatulence, gas, bloating and/or diarrhea. On the other side the available evidence is really limited and further clinical studies will have to confirm what preliminarily observed in relatively small patient samples to determine the cost/benefit ratio and therapeutic features of this ‘new’ source of omega 3 and natural antioxidants. In particular, studies are needed to confirm in humans very interesting data available on animal model on liver steatosis. In fact, diet supplementation with Krill oil in rats fed a high-fat diet reduced the activity and expression of mitochondrial citrate carrier,

thereby decreasing the amount of substrate available for hepatic fatty acid synthesis. A similar effect was also observed when animals were fed with a standard diet, suggesting that Krill oil has an intrinsic capability to reduce hepatic lipogenesis [19] . Then, besides the inhibition of de novo lipogenesis, a marked increase in fatty acid oxidation was observed in animals fed with a diet enriched in Krill oil. Thus, Krill oil stimulated the catabolization of excess fat introduced by a hypercaloric diet, while inhibiting de novo fatty acid synthesis and therefore preventing the onset of fatty liver [20] . These data have however to be yet confirmed in clinical trials.

References

10

Matias I, Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V. Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: effect of high fat diets. Mol. Cell. Endocrinol. 286, S66–S78 (2008).

11

Annuzzi G, Piscitelli F, Di Marino L et al. Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients. Lipids Health Dis. 9, 43 (2010).

12

Di Marzo V, Cote M, Matias I et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia 52, 213–217 (2009).

13

Sipe JC, Scott TM, Murray S et al. Biomarkers of endocannabinoid system activation in severe obesity. PLoS ONE 5, e8792 (2010).

14

Banni S, Carta G, Murru E et al. Krill oil significantly decreases 2-arachidonoylglycerol plasma levels in obese subjects. Nutr. Metab. 8, 7 (2011).

15

Sampalis F, Bunea R, Pelland MF, Kowalski O, Duguet N, Dupuis S. Evaluation of the effects of Neptune Krill Oil™ on the Management of premenstrual syndrome and dysmenorrhea. Alt. Med. Rev. 8, 171–179 (2003).

16

Konagai C, Yanagimoto K, Hayamizu K, Han L, Tsuji T, Koga Y. Effects of krill oil containing n-3 polyunsaturated fatty acids in phospholipid form on human brain function: a randomized controlled trial in healthy elderly volunteers. Clin. Interv. Aging 8, 1247–1257 (2013).

17

Kidd PM. Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids. Alt. Med. Rev. 12, 207–227 (2007).

1

Cicero AF, De Sando V, Parini A, Borghi C. Polyunsaturated fatty acids application in internal medicine: beyond the established cardiovascular effects. Arch. Med. Sci. 8, 784–793 (2012).

2

Cicero AF, Ertek S, Borghi C. Omega-3 polyunsaturated fatty acids: their potential role in blood pressure prevention and management. Curr. Vasc. Pharmacol. 7, 330–337 (2009).

3

Cicero AF, Morbini M, Borghi C. Do we need “new” omega 3 polyunsaturated fatty acids formulations? Exp. Opin. Pharmacother. (2015) (In Press).

4

Ramprasath VR, Eyal I, Zchut S, Jones PJH. Enhanced increase of omega 3 index in healthy individuals with response to 4 week n-3 fatty acid supplementation from krill oil versus fish oil. Lipids Health Dis. 12, 178 (2013).

5

Naguib YM. Antioxidant activities of astaxanthin and related carotenoids. J. Agric. Food Chem. 48, 1150–1154 (2000).

6

Ulven SM, Kirkhus B, Lamglait A et al. Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of EPA and DHA, in healthy volunteers. Lipids 46, 37–46 (2011).

7

Bunea R, El Farrah K, Deutsch L. Evaluation of the Effects of neptune krill oil on the clinical course of hyperlipidemia. Alt. Med. Rev. 9, 420–428 (2004).

8

Berge K, Piscitelli F, Hoem N et al. Chronic treatment with krill powder reduces plasma triglyceride and anandamide levels in mildly obese men. Lipids Health Dis. 12, 78 (2013).

9

Deutsch L. Evaluation of the effect of Neptune Krill Oil on chronic inflammation and arthritic symptoms. J. Am. Coll. Nutr. 26, 39–48 (2007).


Editorial

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

www.futuremedicine.com

3

Editorial Cicero & Colletti 18

19

4

Westerhof W, van Ginkel CJ, Cohen EB, Mekkes JR. Prospective randomized study comparing the debriding effect of krill enzymes and a non-enzymatic treatment in venous leg ulcers. Dermatologica 181, 293–297 (1990). Ferramosca A, Zara V. A krill oil supplemented diet reduces the activities of the mitochondrial tricarboxylate carrier and

Clin. Lipidol. (2015) 10(1)

of the cytosolic lipogenic enzymes in rats. J. Anim. Physiol. Anim. Nutr. 96, 295–306 (2012). 20

Ferramosca A, Zara V. Modulation of hepatic steatosis by dietary fatty acids. World J. Gastroenterol. 20, 1746–1755 (2014).
