Incorporation of long‐chain n‐3 fatty acids in tissues and enhanced bone marrow cellularity with docosahexaenoic acid feeding in post‐weanling Fischer 344 rats

Abstract

We wanted to examine the effects of an oil rich in docosahexaenoic acid (DHA), without eicosapentaenoic acid, on the composition of membrane phospholipid in a variety of tissues. Our in vitro studies had previously shown that DHA could modify glucose and nucleoside transport in cells in culture and also increase selectivity of the nucleoside drug, arabinosylcytosine (araC) toward tumor cells. Here we wanted to examine what effect DHA supplementation would have in the whole animal in terms of the chemosensitivity of normal bone marrow, the dose-limiting tissue during chemotherapy, to araC. The purpose was to determine whether fatty acid supplementation might be useful as an adjuvant to chemotherapy. We fed diets containing 5% (w/w) low fat-corn oil (LF-CO group), 10% moderate fat-safflower oil (MF-SO group), or 10% DHASCO (MF-DHA group) to weanling Fischer 344 rats for 8-9 wk. Feed intake and growth were not different between the different diets. Similarly, treatment of animals with the chemotherapeutic drug araC did not differentially affect growth, feed intake, or tissue fatty acid composition for the different diet groups. Fatty acid compositions of bone marrow, liver, red blood cells, plasma phospholipid and triglyceride, as well as skeletal and cardiac muscle, were substantially different between the dietary groups. The DHASCO oil contained 46% DHA (22:6n-3) and resulted in profound incorporation of DHA in all tissues examined. The most dramatic response was seen in skeletal muscle of MF-DHA fed animals where DHA represented 46% of membrane phospholipid fatty acids. This is likely to have consequences to muscle function. Although DHASCO contains a similar level of saturated fatty acids (42%), few differences in saturates were noted between the various dietary groups for most of the tissues examined. Both LF-CO and MF-SO diets were hypercholesterolemic, and the LF-CO was also hypertriglyceridemic compared to the chow-fed animals. Animals fed the MF-DHA diet had the lowest triglyceride levels of any of the treatment groups and cholesterol levels comparable to chow-fed animals. MF-DHA had substantially higher numbers of colony-forming units-granulocyte macrophage (CFU-GM) as reflected in a twofold higher bone marrow cellularity than either chow or LF-CO animals, suggesting expansion of the bone marrow compartment with DHA feeding. Although higher than LF-SO, the number of CFU-GM in MF-SO animals was not significantly higher than animals fed chow. Bone marrow from LF-CO animals appeared to be more resistant to araC treatment than either MF group. Thus, DHA, fed as DHASCO, has advantages over low or moderate n-6 diets and chow as it is has both hypolipidemic- and bone marrow-enhancing properties in weanling Fischer 344 rats. This suggests that DHA supplementation may be useful in adjuvant chemotherapy.

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…Diagram adapted from Poulsen and Kruger (2007) [152]. [12,13]. In line with this finding, the PUFA composition of cell membranes is dependent on the dietary intake to a great extent.…”

“…AA preserves MSC numbers through COX-2 mediated synthesis of PGE 2 by inhibiting apoptosis [70]. DHA and possibly also other n-3 LCPUFA-rich diets may elevate or preserve bone mass through increasing MSC numbers [13] and through enhanced expression of key transcription factors such as Cbfa1 and osterix [33,92] that enhance differentiation of pre-osteoblasts into mature osteoblasts. Expression of both Cbfa1 and osterix is enhanced by IGF-1, TGF-β1, BMP and moderate amounts of PGE 2 [92], all of which result from diets rich in n-3 LCPUFA.…”

“…Atkinson et al [13] demonstrated that feeding post-weanling male Fisher rats DHA had substantial bone marrow enhancing activity, resulting in a two-fold increase in bone marrow cell number over n-6 PUFA fed animals. Bone marrow contains various precursor cells including mesenchymal stem cells that are able to differentiate into several cell types including osteoblasts and adipocytes [86,87].…”

Inflammation, Osteoporosis and Atherosclerosis: The Tsimtsoum Concept

“…In another study [23], an increased production of PGE2 in tibia of chicks given a semipurified diet containing soya bean oil, high in w-6 fat was associated with a lower rate of bone formation compared with that of chicks fed a low dietary ratio of w-6/w-3 fatty acids. In a further study [24], rats fed with a lower dietary ratio of w-6/w-3 fat showed increased bone marrow cellularity and bone strength. These studies indicate that w-6/w-3 fatty acid ratio of diet appears to be important in bone metabolism, and may be responsible for fracture due to trivial trauma in our patients.…”

“…Further support for the role of polyunsaturated fatty acids in the pathogenesis of osteoporosis and hip fracture may be provided from the experimental studies [22][23][24][25]. In a experimental study [22], 15 rats were fed identical diets except that w-6/w-3 ratio differed.…”