DHA (docosahexaenoic acid) is an omega-3 fatty acid that is absolutely essential for the normal function of the brain, and its deficiency is known to be associated with several neurological disorders including Alzheimer's disease (AD), mental retardation, and schizophrenia. Although the brain contains the highest concentration of DHA among the organs, it is unable to synthesize DHA from the precursors, and needs to obtain it mostly from the diet. However, the presently available dietary supplements (fish oil, ethyl esters, krill oil, etc.) are inefficient in increasing the brain DHA levels, although they all easily enric the other organs with DHA. One possible reason for this is that while all other organs take up DHA in the form of whole lipoprotein particles, the brain takes it up through molecular diffusion of th DHA-containing lipids through the blood brain barrier, the most efficient carrier of DHA being lysophosphatidylcholine (LPC). Thus, the presence of DHA in plasma phospholipids is crucial for its brain uptake, and consequently, the absorption of dietary DHA in the form of phospholipids, rather than as triacylglycerol (TG), is highly advantageous. However, the presently available supplements of DHA are all absorbed as TG, because DHA in them is released as free fatty acid in the intestinal lumen by the pancreatic lipase and phospholipase A2, and incorporated into chylomicron TG. In this exploratory project, we will test the hypothesis that supplying the DHA as the sn-1 ester of phosphatidylcholine (PC) would result in its absorption as phospholipid because it escapes hydrolysis by the pancreatic enzymes, and thus will be more available for the eventual uptake by the brain.
In Aim 1, we will study the absorption of different molecular forms of DHA (free acid, TG, sn-1 ester of PC, sn-2 ester of PC, and as LPC) employing an in vitro model (Caco-2 cells) as well as an in vivo model (lymph fistula rat). The relative amounts of DHA found in TG and PC of the absorbed lipids will be determined by tandem mass spectroscopy and gas chromatography.
In Aim 2, we will feed the various molecular forms of DHA as supplements to the normal diets of adult rats for 4 weeks, and determine its appearance in plasma phospholipids, as well as its accumulation in the liver, adipose tissue and brain. If the proposed hypothesis is correct, the accumulation of DHA in the brain should be highest when it is present in the diet as sn-1 ester of PC or LPC. The results from these studies could lead to novel nutraceutical approaches to achieve adequate brain DHA levels for healthy aging and for prevention of neurological diseases such as AD, mental retardation, and schizophrenia.
This proposal aims to identify the best possible dietary supplement to increase levels of brain DHA, an omega- 3 fatty acid that is essential for normal brain function and healthy aging. The studies proposed here will test the hypothesis that the bioavailability of DHA to the brain is increased if it is supplied as a specific form of phospholipd in the diet. The results from these studies could lead to novel dietary supplements to improve brain function and prevent neurological diseases such as Alzheimer's.
|Cordoba-Chacon, Jose; Sarmento-Cabral, Andre; Del Rio-Moreno, Mercedes et al. (2018) Adult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction. Endocrinology 159:3761-3774|
|Wolf Greenstein, Abigail; Majumdar, Neena; Yang, Peng et al. (2017) Hepatocyte-specific, PPAR?-regulated mechanisms to promote steatosis in adult mice. J Endocrinol 232:107-121|
|Sugasini, Dhavamani; Thomas, Riya; Yalagala, Poorna C R et al. (2017) Dietary docosahexaenoic acid (DHA) as lysophosphatidylcholine, but not as free acid, enriches brain DHA and improves memory in adult mice. Sci Rep 7:11263|
|Ayee, Manuela A A; LeMaster, Elizabeth; Shentu, Tzu Pin et al. (2017) Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids. Biophys J 112:325-338|
|Sugasini, Dhavamani; Subbaiah, Papasani V (2017) Rate of acyl migration in lysophosphatidylcholine (LPC) is dependent upon the nature of the acyl group. Greater stability of sn-2 docosahexaenoyl LPC compared to the more saturated LPC species. PLoS One 12:e0187826|
|Subbaiah, Papasani V; Dammanahalli, Karigowda J; Yang, Peng et al. (2016) Enhanced incorporation of dietary DHA into lymph phospholipids by altering its molecular carrier. Biochim Biophys Acta 1861:723-9|
|Kineman, Rhonda D; Majumdar, Neena; Subbaiah, Papasani V et al. (2016) Hepatic PPAR? Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice. Endocrinology 157:1728-35|
|Yang, Peng; Subbaiah, Papasani V (2015) Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins. Biochim Biophys Acta 1851:1327-36|