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Maternal hypercholesterolemia (MHC) is a pathological condition characterized by an exaggerated rise in maternal serum cholesterol during gestation, which can alter offspring hepatic lipid metabolism. However, the extent that these maladaptations occur during gestation and the molecular mechanisms involved remain unknown. MicoRNAs (miRNA) are small, noncoding RNAs that contribute to the development and progression of nonalcoholic fatty liver disease. Therefore, we sought to determine the degree to which in utero exposure to excessive cholesterol affects fetal hepatic lipid metabolism and miRNA expression. Twelve female apoE-/- mice were randomly assigned to two different chow-based diets throughout gestation: control (CON) or the CON diet with cholesterol (0.15%). MHC reduced maternal fecundity and reduced litter size and weight. On gestational day 18, fetuses from MHC dams possessed increased placental cholesterol and hepatic triglycerides (TG), which were accompanied by a downregulation in the expression of hepatic lipogenic and TG synthesis and transport genes. Furthermore, fetal livers from MHC mothers showed increased miRNA-27a and reduced miRNA-200c expression. In summary, in utero exposure to MHC alters fetal lipid metabolism and lends mechanistic insight that implicates early changes in miRNA expression that may link to later-life programming of disease risk. [ABSTRACT FROM AUTHOR]

Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We characterized the hypolipidemic effects of alpha-lipoic acid (LA, R-form) and examined the associated molecular mechanisms in a high fat fed Zucker rat model. Rats (n = 8) were assigned to a high fat (HF) diet or the HF diet with 0.25% LA (HF-LA) for 30 days and pair fed to remove confounding effects associated with the anorectic properties of LA. Compared with the HF controls, the HF-LA group was protected against diet-induced obesity (102.5±3.1 vs. 121.5±3.6,% change BW) and hypercholesterolemia with a reduction in total-C (−21%), non-HDL-C (−25%), LDL-C (−16%), and total LDL particle number (−46%) and an increase in total HDL particles (∼22%). This cholesterol-lowering response was associated with a reduction in plasma PCSK9 concentration (−70%) and an increase in hepatic LDLr receptor protein abundance (2 fold of HF). Compared with the HF-fed animals, livers of LA-supplemented animals were protected against TG accumulation (−46%), likely through multiple mechanisms including: a suppressed lipogenic response (down-regulation of hepatic acetyl-CoA carboxylase and fatty acid synthase expression); enhanced hepatic fat oxidation (increased carnitine palmitoyltransferase Iα expression); and enhanced VLDL export (increased hepatic diacylglycerol acyltransferase and microsomal triglyceride transfer protein expression and elevated plasma VLDL particle number). Study results also support an enhanced fatty acid uptake (2.8 fold increase in total lipase activity) and oxidation (increased CPT1β protein abundance) in muscle tissue in LA-supplemented animals compared with the HF group. In summary, in the absence of a change in caloric intake, LA was effective in protecting against hypercholesterolemia and hepatic fat accumulation under conditions of strong genetic and dietary predisposition toward obesity and dyslipidemia. [ABSTRACT FROM AUTHOR]

Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Maternal hypercholesterolemia (MHC), a pathological condition characterized by an exaggerated rise in maternal serum cholesterol during pregnancy, may influence offspring hepatic lipid metabolism and increase the risk of nonalcoholic fatty liver disease (NAFLD). As NAFLD is characterized by a sexual dimorphic response, we assessed whether early-life exposure to excessive cholesterol influences the development of NAFLD in offspring and whether this occurs in a sex-specific manner. Female apoE-/- mice were randomly assigned to a control (CON) or a high cholesterol (CH; 0.15%) diet prior to breeding. At parturition, a cross-fostering approach was used to establish three groups: (1) normal cholesterol exposure throughout gestation and lactation (CON-CON); (2) excessive cholesterol exposure throughout gestation and lactation (CH-CH); and (3) excessive cholesterol exposure in the gestation period only (CH-CON). Adult male offspring (PND 84) exposed to excessive cholesterol during gestation only (CH-CON) demonstrated hepatic triglyceride (TG) accumulation and reduced lipogenic gene expression. However, male mice with a prolonged cholesterol exposure throughout gestation and lactation (CH-CH) had a similar, but not exacerbated hepatic response. Further, with the exception of higher serum TG in adult CH-CH females, evidence for a programming effect in female offspring was largely absent in comparison with males. These results indicate a sexual dimorphic response with respect to the effect of MHC on later life hepatic steatosis and highlight the gestation period as the most influential malprogramming window for hepatic lipid dysfunction in males. [ABSTRACT FROM AUTHOR]

In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE-/- mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P˂.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7αHC, 7βHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid-lowering option during hypercholesterolemic pregnancies for which there are currently limited options. [ABSTRACT FROM AUTHOR]

Abstract: Background: Information is scarce regarding the effect of dietary protein type, with specific focus on the lysine-to-arginine (Lys:Arg) ratio, on cardiovascular risk factors and vascular reactivity in humans. Objective: Determine the effect of dietary Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults. Design: Randomized cross-over design of two 35-day diet phases; thirty adults (21 females and 9 males, ≥50 years, LDL cholesterol ≥120mg/dL). Diets had 20% energy (E) protein, 30%E fat, 50%E carbohydrate and were designed to have low (0.7) or high (1.4) Lys:Arg ratio. Measures included fasting and postprandial lipid, lipoprotein, apolipoprotein concentrations; fasting high sensitivity C-reactive protein (hsCRP), small dense LDL (sdLDL) cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities; cholesterol fractional synthesis rate (FSR); and flow mediated dilation (FMD) and peripheral artery tonometry (PAT). Results: No differences were observed in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or PAT. The low, relative to the high, Lys:Arg ratio diet resulted in lower postprandial VLDL cholesterol (−24%, P =0.001) and triglycerides (−23%, P =0.001), and small but significant differences in fasting (−3%, P =0.003) and postprandial (−3%, P =0.018) apo AI, and fasting adiponectin concentrations (+7%, P =0.035). Fasting and postprandial hsCRP concentrations were 23% lower after the low Lys:Arg ratio diet (P =0.020 for both). Conclusions: Diets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity. [Copyright &y& Elsevier]