Role of n-3 Fatty Acids on Bile Acid Metabolism and Transport in Dyslipidemia: A Review.

Dietary n-3 fatty acids, especially of marine origin, eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3), have always been lauded for their profound effects on regulating the risk factors for major metabolic disorders. Yet, their consumption rate is poor compared to n-6 fatty acids [linoleic acid (18:2n-6)], which are predominantly consumed. Hence, the skewed n-6 to n-3 fatty acid ratio may have a bearing on the risk factors of various diseases, including dyslipidemia. Dyslipidemia and other lifestyle diseases associated with it, such as diabetes, obesity, hypertension, are a growing concern in both developed and developing countries. A common strategy for addressing dyslipidemia involves bile acid (BA) sequestration, to interrupt the enterohepatic circulation of BA, resulting in the modulation of lipid absorption in the intestine, thereby normalizing the levels of circulating lipids. The BA homeostasis is under the tight control of hepatic and enteric BA transporters. Many investigations have reported the effects of dietary constituents, including certain fatty acids on the reabsorption and transport of BA. However, a critical review of the effects of n-3 fatty acids on BA metabolism and transport is not available. The present review attempts to explore certain unmapped facets of the n-3 fatty acids on BA metabolism and transport in dyslipidemia, and their interplay with biological processes involving lipid rafts and gut microbiome.

n-3 Fatty Acids Abrogate Dyslipidemia-Induced Changes in Bile Acid Uptake, Synthesis, and Transport in Young and Aged Dyslipidemic Rats.

In this study, the effect of n-3 fatty acids (FA) [α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] on the intestinal bile acid (BA) uptake, hepatic BA synthesis, and enterohepatic bile acid transporters (BAT) was assessed in young and aged dyslipidemic rats. Dyslipidemia was induced in young and aged rats by feeding a high-fat (HF) diet. Experimental groups received diets containing canola oil (HF + CNO) and fish oil (HF + FO) as a source of ALA and EPA + DHA, respectively. After 60 days of feeding, intestinal BA uptake and expression of apical sodium-dependent bile acid transporter (Asbt), organic solute transporter-alpha/beta (Osta/b) messenger RNA (mRNA), and hepatic expression of Na+ taurocholate cotransporting polypeptide (Ntcp), bile salt export pump (Bsep), cholesterol 7-α hydroxylase A1 (Cyp7a1), Farnesoid X receptor (Fxr), small heterodimer partner-1 (Shp), liver receptor homolog-1 (Lrh-1), and hepatic nuclear factor-4 alpha (Hnf4a) mRNA were measured. Hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity and total BA in serum, liver, and feces were assessed. The dyslipidemic HF group had: (1) increased intestinal BA uptake and Asbt and Osta/b mRNA expression, (2) increased BA in serum, (3) decreased hepatic expression of Ntcp, Bsep, and Cyp7a1 mRNA, (4) increased activity of HMG-CoA reductase, (5) increased hepatic expression of Fxr and Shp mRNA, (6) decreased hepatic expression of Lrh-1 and Hnf4a mRNA, and (7) decreased BA in feces, when compared to control, HF + CNO, and HF + FO groups. Immunostaining revealed increased expression of intestinal Asbt and hepatic Ntcp protein in the HF group when compared to control, HF + CNO, and HF + FO groups. n-3 FA abrogated dyslipidemia-induced changes in the intestinal uptake, hepatic synthesis, and enterohepatic transporters of BA in both young and aged rats. EPA + DHA was more effective than ALA in modulating dyslipidemia-induced changes.

Marrow-derived cells regulate the development of early diabetic retinopathy and tactile allodynia in mice.

The hypothesis that marrow-derived cells, and specifically proinflammatory proteins in those cells, play a critical role in the development of diabetes-induced retinopathy and tactile allodynia was investigated. Abnormalities characteristic of the early stages of retinopathy and allodynia were measured in chimeric mice lacking inducible nitric oxide synthase (iNOS) or poly(ADP-ribosyl) polymerase (PARP1) in only their marrow-derived cells. Diabetes-induced capillary degeneration, proinflammatory changes, and superoxide production in the retina and allodynia were inhibited in diabetic animals in which iNOS or PARP1 was deleted from bone marrow cells only. Of the various marrow cells, neutrophils (and monocytes) play a major role in retinopathy development, because retinal capillary degeneration likewise was significantly inhibited in diabetic mice lacking the receptor for granulocyte colony-stimulating factor in their marrow-derived cells. Immunodepletion of neutrophils or monocytes inhibited the endothelial death otherwise observed when coculturing leukocytes from wild-type diabetic animals with retinal endothelium. iNOS and PARP1 are known to play a role in inflammatory processes, and we conclude that proinflammatory processes within marrow-derived cells play a central role in the development of diabetes complications in the retina and nerve.

Lower efficacy in the utilization of dietary ALA as compared to preformed EPA + DHA on long chain n-3 PUFA levels in rats.

We made a comparative analysis of the uptake, tissue deposition and conversion of dietary alpha-linolenic acid (ALA) to its long chain metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with preformed EPA + DHA. Diets containing linseed oil [with ALA at approximately 2.5 (4 g/kg diet), 5 (8 g/kg diet), 10 (16 g/kg diet), 25% (40 g/kg diet)] or fish oil [with EPA + DHA at approximately 1 (1.65 g/kg diet), 2.5 (4.12 g/kg diet), 5% (8.25 g/kg diet)] or groundnut oil without n-3 polyunsaturated fatty acids (n-3 PUFA) were fed to rats for 60 days. ALA and EPA + DHA in serum, liver, heart and brain increased with increments in the dietary ALA level. When preformed EPA + DHA were fed, the tissue EPA + DHA increased significantly compared to those given ALA. Normalized values from dietary n-3 PUFA to tissue EPA + DHA indicated that 100 mg of dietary ALA lead to accumulation of EPA + DHA at 2.04, 0.70, 1.91 and 1.64% of total fatty acids respectively in liver, heart, brain and serum. Similarly 100 mg of preformed dietary EPA + DHA resulted in 25.4, 23.8, 15.9 and 14.9% of total fatty acids in liver, heart, brain and serum respectively. To maintain a given level of EPA + DHA, the dietary ALA required is 12.5, 33.5, 8.3 and 9.1 times higher than the dietary EPA + DHA for liver, heart, brain and serum respectively. Hence the efficacy of precursor ALA is lower compared to preformed EPA + DHA in elevating serum and tissue long chain n-3 PUFA levels.