Plasma fatty acids in premature infants with hyperbilirubinemia: before-and-after nutrition support with fish oil emulsion.

Infants who are dependent on parenteral nutrition (PN) sometimes develop PN-associated cholestasis (PNAC). A compassionate use protocol, approved by the U.S. Food and Drug Administration and the institutional review board, guided enrollment of hospitalized infants with PNAC (<1 year of age, PN dependence for >3 weeks). Plasma concentrations of essential fatty acids were monitored before and after a soybean-based PN lipid, infused at 3 g/kg body weight/d, was replaced by an experimental fish oil-based intravenous fat emulsion (FO-IVFE) at 1.0 g/kg/d. All participants were born premature (n = 10; 20% male). At enrollment, infants were (mean ± SD) 86.5 ± 53.5 days of life and weighed 2.24 ± 0.87 kg; direct bilirubin was 5.5 ± 1.3 mg/dL. After treatment, blood concentrations significantly increased from baseline (P < .017) for circulating eicosapentaenoic acid (6.3 ± 3.0 to 147.8 ± 53.1 µg/mL), docosahexaenoic acid (20.7 ± 6.5 to 163.7 ± 43.4 µg/mL), pristanic acid (0.01 ± 0.01 to 0.17 ± 0.03 µg/mL), and phytanic acid (0.06 ± 0.03 to 0.64 ± 0.15 µg/mL). In contrast, total plasma ω-6 fatty acids (including linoleic acid) decreased (P < .017). The triene/tetraene ratio remained below the threshold value of 0.2 that defines ω-6 deficiency. No adverse effects were observed attributable to FO-IVFE. Discontinuation of FO-IVFE was typically due to infants (body weight 3.76 ± 1.68 kg) transitioning to enteral feeding rather than for resolution of hyperbilirubinemia (direct bilirubin 7.9 ± 4.8 mg/dL). These exploratory results suggest that FO-IVFE raises circulating ω-3 fatty acids in premature infants without development of ω-6 deficiency in the 8.3 ± 5.8-week time frame of this study.

Arterial retention of remnant lipoproteins ex vivo is increased in insulin resistance because of increased arterial biglycan and production of cholesterol-rich atherogenic particles that can be improved by ezetimibe in the JCR:LA-cp rat.

BACKGROUND: Literature supports the "response-to-retention" hypothesis-that during insulin resistance, impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. We used the JCR:LA-cp rat model of metabolic syndrome (MetS) to determine the extent of arterial accumulation of intestinal-derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance. METHODS AND RESULTS: Arteries from control and MetS (insulin-resistant) JCR:LA-cp rats were perfused ex vivo with Cy5-labeled remnant lipoproteins, and their arterial retention was quantified by confocal microscopy. Arterial proteoglycans were isolated from control and MetS rats at 6, 12, and 32 weeks of age. There was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in MetS rats as compared to control rats. Mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol-rich intestinal-derived remnants, as compared to controls. Additionally, perfusion of vessels treated with ezetimibe, alone or in combination with simvastatin, with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant-derived cholesterol ex vivo as compared to untreated controls. CONCLUSIONS: Increased progression of atherosclerotic cardiovascular disease in MetS and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol-rich remnants. Furthermore, ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and MetS.

Chronic dietary n-3 PUFA intervention improves dyslipidaemia and subsequent cardiovascular complications in the JCR:LA- cp rat model of the metabolic syndrome.

There is increasing interest in the potential chronic beneficial effects of dietary n-3 PUFA on the metabolic syndrome (MetS) and associated cardiovascular complications. We have recently established that increased dietary n-3 PUFA has a profound acute benefit on fasting lipids and the postprandial pro-inflammatory response in the JCR:LA-cp rat, a model of the MetS. However, it is unclear to what extent chronic dietary n-3 PUFA intervention can modulate the progression of end-stage metabolic and vascular complications. The present study aimed to determine the chronic effects of dietary n-3 PUFA supplementation on fasting and non-fasting dyslipidaemia, insulin resistance and vascular complications in the JCR:LA-cp rodent model. JCR:LA-cp rats were fed an isoenergetic lipid-balanced diet supplemented with 5 % n-3 PUFA (w/w) of the total fat (fish oil-derived EPA/DHA) for 16 weeks. Fasting and non-fasting (postprandial) plasma lipid profile was assessed. Hepatic and adipose tissue was probed for the expression of lipogenic proteins (acyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1 (SREBP-1)), while the activity of Jun N-terminal kinase (JNK) was assessed via Western blot to target phosphorylated JNK protein in primary enterocytes. The frequency of myocardial lesions was assessed by haematoxylin and eosin staining. Increased dietary n-3 PUFA improved both the fasting and postprandial lipid profiles (TAG, cholesterol and apoB48) in the JCR:LA-cp rat, potentially via the down-regulation of the hepatic or adipose tissue expression of lipogenic enzymes (ACC, FAS and SREBP-1). Rats fed the 5 % n-3 PUFA diet had lower (58·2 %; P < 0·01) enterocytic phosphorylated JNK protein and secreted less cholesterol (30 %; P < 0·05) into mesenteric lymph compared with the control. The chronic metabolic benefits of dietary n-3 PUFA may underlie the potential to reduce vascular complications during the MetS, including the observed reduction in the frequency (approximately 80 %) of late-stage 3 myocardial lesions.

Growth hormone action in the developing neural retina: a proteomic analysis.

The possible presence and action of growth hormone (GH) in the neural retina was investigated in newborn mice. The neural retina was found to be a site of GH gene expression, as GH mRNA was abundant in cells of the retinal ganglion cell layer, in which GH was also detected. It was also a site of GH action, since GH receptor (GHR) immunoreactivity mirrored that of GH. Actions of GH within the eye were indicated by a reduction in its axial length and retinal width (its neuroblastic, inner plexiform, and optic fiber layers) in GHR gene disrupted mice (GHR-/-), in comparison with wild type (GHR+/+) littermates. In the absence of GH signaling, four proteins in the retinal proteome of the GHR-/- mice (identified by 2-D gels and MS) differed in abundance with those in the wild type mice. Brain abundant membrane attached signal protein-1 (BASP-1) was down-regulated, whereas protein kinase C inhibitor 1, cyclophilin A, KH domain-containing, RNA-binding, signal transduction-associated protein 3 were up-regulated in GHR-/- mice. These proteins are involved in retinal vascularization, neural proliferation and neurite outgrowth. GH might thus have hitherto unsuspected roles in these processes during retinal development.