Omega-3 fatty acids reduce lipopolysaccharide-induced abnormalities in expression of connexin-40 in aorta of hereditary hypertriglyceridemic rats.

Omega-3 fatty acids (omega3FA) are known to reduce hypertriglyceridemia- and inflammation-induced vascular wall diseases. However, mechanisms of their effects are not completely clear. We examined, whether 10-day omega3FA diet can reduce bacterial lipopolysaccharide-induced changes in expression of gap junction protein connexin40 (Cx40) in the aorta of hereditary hypertriglyceridemic (hHTG) rats. After administration of a single dose of lipopolysaccharide (LPS, 1 mg/kg, i.p.) to adult hHTG rats, animals were fed with omega3FA diet (30 mg/kg/day) for 10 days. LPS decreased Cx40 expression that was associated with reduced acetylcholine-induced relaxation of aorta. Omega3FA administration to LPS rats had partial anti-inflammatory effects, associated with increased Cx40 expression and improved endothelium dependent relaxation of the aorta. Our results suggest that 10-day omega3FA diet could protect endothelium-dependent relaxation of the aorta of hHTG rats against LPS-induced damage through the modulation of endothelial Cx40 expression.

Congenital lipodystrophies and dyslipidemias.

Lipodystrophies are rare acquired and genetic disorders characterized by the selective loss of adipose tissue. One key metabolic feature of patients with congenital inherited lipodystrophy is hypertriglyceridemia. The precise mechanisms by which the lack of adipose tissue causes dyslipidemia remain largely unknown. In recent years, new insights have arisen from data obtained in vitro in adipocytes, yeast, drosophila, and very recently in several genetically modified mouse models of generalized lipodystrophy. A common metabolic pathway involving accelerated lipolysis and defective energy storage seems to contribute to the dyslipidemia associated with congenital generalized lipodystrophy syndromes, although the pathophysiological changes may vary with the nature of the mutation involved. Therapeutic management of dyslipidemia in patients with lipodystrophy is primarily based on specific approaches using recombinant leptin therapy. Preclinical studies suggest a potential efficacy of thiazolidinediones that remains to be assessed in dedicated clinical trials.

Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.

Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole-exome sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated HTG, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycerides in gastrointestinal mucosal injury.

Fetal and neonatal exposure to nicotine leads to augmented hepatic and circulating triglycerides in adult male offspring due to increased expression of fatty acid synthase.

While nicotine replacement therapy is assumed to be a safer alternative to smoking during pregnancy, the long-term consequences for the offspring remain elusive. Animal studies now suggest that maternal nicotine exposure during perinatal life leads to a wide range of adverse outcomes for the offspring including increased adiposity. The focus of this study was to investigate if nicotine exposure during pregnancy and lactation leads to alterations in hepatic triglyceride synthesis. Female Wistar rats were randomly assigned to receive daily subcutaneous injections of saline (vehicle) or nicotine bitartrate (1mg/kg/day) for two weeks prior to mating until weaning. At postnatal day 180 (PND 180), nicotine exposed offspring exhibited significantly elevated levels of circulating and hepatic triglycerides in the male offspring. This was concomitant with increased expression of fatty acid synthase (FAS), the critical hepatic enzyme in de novo triglyceride synthesis. Given that FAS is regulated by the nuclear receptor Liver X receptor (LXRα), we measured LXRα expression in both control and nicotine-exposed offspring. Nicotine exposure during pregnancy and lactation led to an increase in hepatic LXRα protein expression and enriched binding to the putative LXRE element on the FAS promoter in PND 180 male offspring. This was also associated with significantly enhanced acetylation of histone H3 [K9,14] surrounding the FAS promoter, a hallmark of chromatin activation. Collectively, these findings suggest that nicotine exposure during pregnancy and lactation leads to an increase in circulating and hepatic triglycerides long-term via changes in the transcriptional and epigenetic regulation of the hepatic lipogenic pathway.

A maternal diet rich in fish oil may improve cardiac Akt-related signaling in the offspring of diabetic mother rats.

OBJECTIVE: Newborns of diabetic mothers have abnormal circulatory organs, so in this study, we explore insulin signaling in the newborn rat heart. METHODS: Pregnant rats were divided into streptozotocin-induced diabetic groups (DM) and control groups (CM). Rats were fed lard (21% fat), fish oil (21% fat), or a control diet (7% fat). To examine changes in insulin signaling in the hearts of infants of diabetic mothers (IDM) in relation to diet, we isolated the hearts from the IDM and control infants and determined the phosphorylation levels of Akt308, Akt473, p38, c-jun-NH2-terminal protein kinase (JNK), and extracellular signal-regulated protein kinase (ERK), and the expression levels of phosphoinositide-dependent protein kainase1 (PDK1) and mammalian target of rapamycin (mTOR). RESULTS: The mean blood glucose levels in the DM group and their infants were significantly higher than those in the CM group (P < 0.05) and their infants (P < 0.05), but the mean blood glucose levels of all infants was normal on postnatal d 4. Phosphorylation levels of Akt (Thr 308) (P < 0.05) and Akt (Ser 473) and the expression levels of PDK1 and mTOR were lower in infants of diabetic mothers (IDM) than in control infants. The phosphorylation level of Akt (Ser 473) and the expression level of mTOR increased in IDM fed the fish oil diet compared with those fed the lard diet (P < 0.05). CONCLUSION: A maternal diet rich in fish oil improves cardiac Akt-related signaling in the offspring of diabetic rats.

Transgenerational metabolic outcomes associated with uteroplacental insufficiency.

Intrauterine growth restriction increases adult metabolic disease risk with evidence to suggest that suboptimal conditions in utero can have transgenerational effects. We determined whether impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits are evident in second-generation (F2) male and female offspring from growth-restricted mothers, in a rat model of uteroplacental insufficiency. Late gestation uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted) or sham surgery (control) in Wistar-Kyoto rats. First-generation (F1) control and restricted females were mated with normal males and F2 offspring studied at postnatal day 35 and at 6 and 12 months. F2 glucose tolerance, insulin secretion, and sensitivity were assessed at 6 and 12 months and pancreatic morphology was quantified at all study ages. At 6 months, F2 restricted male offspring exhibited blunted first-phase insulin response (-35%), which was associated with reduced pancreatic ß-cell mass (-29%). By contrast, F2 restricted females had increased ß-cell mass despite reduced first-phase insulin response (-38%). This was not associated with any changes in plasma estradiol concentrations. Regardless of maternal birth weight, F2 control and restricted males had reduced homeostatic model assessment of insulin resistance and elevated plasma triglyceride concentrations at 6 months and reduced whole-body insulin sensitivity at 6 and 12 months compared with females. We report that low maternal birth weight is associated with reduced first-phase insulin response and gender-specific differences in pancreatic morphology in the F2. Further studies will define the mode(s) of disease transmission, including direct insults to developing gametes, adverse maternal responses to pregnancy, or inherited mechanisms.

A novel nonsense mutation in the LPL gene in a Chinese neonate with hypertriglyceridemia.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder characterized by hypertriglyceridemia. The genetic defect lies in a mutation of the LPL gene. METHODS: A Chinese neonate with non-consanguineous parents was incidentally found to have hypertriglyceridemia. Mutation in her LPL gene was screened by using polymerase chain reaction and direct DNA sequencing. RESULTS: Homozygous missense mutations (L252V) were detected in the LPL gene of the patient. A novel nonsense mutation (C27X) was also identified. CONCLUSION: Our finding supports L252V mutation in the LPL gene is a common mutation in Chinese with familial hyperchylomicronemia syndrome. DNA-based diagnosis in this syndrome is definitive. It saves the need for heparin-infusion test, which carries the risk of hemorrhage, and the measurement of LPL activity, which is tedious and is not widely available.

Éxito reproductivo en embarazo de madre portadora de diabetes lipoatrófica generalizada / Reproductive successful in pregnancy of mother with generalized lipoatrophic diabetes

Se presenta el caso de una paciente portadora de diabetes lipoatrófica generalizada con éxito reproductivo. Se analiza el tratamiento metabólico y el manejo perinatal. La instalación de infección intraamniótica determinó la interrupción del embarazo a las 28 semanas, con recién nacido de pretérmino adecuado para la edad gestacional, que evolucionó con distrés respiratorio prolongado, hemorragia subaracnoidea y enterocolitis necrotizante. El seguimiento al sexto mes de vida revela examen neurológico normal.

Regulation of gene expression for lipogenic enzymes in the liver and adipose tissue of hereditary hypertriglyceridemic, insulin-resistant rats: effect of dietary sucrose and marine fish oil.

Hypertriglyceridemia is closely linked to insulin resistance. Increased dietary intake of n-3 polyunsaturated fatty acids reverses both hypertriglyceridemia and insulin resistance. To evaluate molecular mechanisms responsible for the hypotriglyceridemic effects of n-3 polyunsaturated fatty acids, the expression of genes for lipogenic enzymes in liver and white and brown adipose tissue was estimated in hereditary hypertriglyceridemic rats which underwent an euglycemic hyperinsulinemic clamp. Before the clamp, animals were fed a basal or a high (63%) sucrose diet with or without fish oil for two weeks. Results were compared to data obtained from control animals subjected to the identical protocol. In hereditary hypertriglyceridemic rats, gene expression for malic enzyme was increased in liver and in brown adipose tissue but not in white adipose tissue. The high sucrose diet raised malic enzyme mRNA levels in liver of both hereditary hypertriglyceridemic and control rats, and this effect was more pronounced in brown adipose tissue. Supplementing the high sucrose diet with fish oil led to a suppression of malic enzyme gene expression in liver and brown adipose tissue of control rats. However, this inhibitory effect was not as pronounced in the hereditary hypertriglyceridemic rats. Raised levels of fatty acid synthase mRNA in liver and brown adipose tissue of control rats fed high sucrose diet were suppressed by consumption of diet high in n-3 fatty acids. On the other hand, in hereditary hypertriglyceridemic rats fed high sucrose diet, fish oil supplementation failed to suppress increased levels of fatty acid synthase mRNA in liver and in brown adipose tissue. It appears that hereditary hypertriglyceridemic rats have elevated levels of mRNA for lipogenic enzymes in liver and brown adipose tissue and dietary control leading to an alteration of hypertriglyceridemia influences gene expression of lipogenic enzymes only under special dietary circumstances.

Hypodipsic hypernatremia and hypertriglyceridemia associated with cleft lip and cleft palate: a new hypothalamic dysfunction syndrome?

We report on a 4-month-old girl with congenital hypodipsic hypernatremia resulting from decreased sensitivity of the hypothalamic osmoreceptors with increased tonicity in association with hyperlipemia and cleft lip and cleft palate. We postulate that the link among these various derangements is hypothalamic dysfunction.