These results suggest that specific inhibition of ASBT is a novel therapeutic approach for treatment of hypercholesterolemia resulting in a decreased risk for atherosclerosis. -

Dietary protein sources in male Golden Syrian hamsters fed a Western diet affect the gut microbiota, and soy protein may reduce lipogenesis through alterations of the gut microbial community.

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To explore the therapeutic efficacy and potential mechanisms of action of a new class of antiatherosclerotic drugs, AGI-1067 [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester] (butanedioc acid) was tested in several animal models of atherosclerosis. AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. In contrast, another phenolic antioxidant, probucol, had a modest LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). Histopathology of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis in LDL receptor-deficient (LDLr Ϫ/Ϫ) mice and apolipoprotein E-deficient (ApoE Ϫ/Ϫ) mice even in the absence of a lipid-lowering effect. In LDLr Ϫ/Ϫ mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE Ϫ/Ϫ mice, AGI-1067 reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited tumor necrosis factor-␣-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC 50 values ϭ 6, 10, and 25 M, respectively). These data show that AGI-1067 can inhibit atherosclerosis not only via its lipid-lowering effects but also by having direct anti-inflammatory effects on the vessel wall and suggest that it may be a novel therapeutic agent for coronary artery disease.

Soy protein is effective at preventing hepatic steatosis; however, the mechanisms are poorly understood. We tested the hypothesis that soy versus dairy protein-based diet would alter microbiota and attenuate hepatic steatosis in hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats were randomized to “Western” diets containing milk protein isolate (MPI), soy protein isolate (SPI), or 50:50 MPI/SPI (MS) (n=9–10/group; 21% kcal protein) for 16 weeks. SPI attenuated (P<0.05) fat mass and percent fat by ~10% compared with MS, but not compared with MPI. Serum TBAR and total and LDL-cholesterol concentrations were lower (P<0.05) with dietary SPI versus MPI and MS. Histological hepatic steatosis was lower (P<0.05) in SPI compared with MPI or MS. Lipidomic analyses revealed reductions (P<0.05) in hepatic diacylglycerols but not triacylglycerols in SPI compared with MPI, which was associated with lower hepatic de novo lipogenesis (ACC, FAS, and SCD-1 protein content, and hepatic 16:1 n-7 and 18:1 n-7 PUFA concentrations) (P<0.05) compared with MPI and MS; however, MPI displayed elevated hepatic mitochondrial function compared with SPI and MS. Fecal bacterial 16S rRNA analysis revealed SPI-intake elicited increases (P<0.05) in Lactobacillus and decreases (P<0.05) in Blautia and Lachnospiraceae suggesting decreases in fecal secondary bile acids in SPI rats. SPI and MS exhibited greater (P<0.05) hepatic Fxr, Fgfr4, Hnf4a, HmgCoA reductase and synthase mRNA expression compared with MPI. Overall, dietary SPI compared with MPI decreased hepatic steatosis and diacylglycerols, changed microbiota populations, and altered bile acid signaling and cholesterol homeostasis in a rodent model of obesity.

Summary Background & aims Blends of dairy and soy protein are used in commercial sports nutrition products; however, no studies have systematically compared blends to isolated protein sources and their effects on muscle protein synthesis (MPS). Dairy whey protein (WP), soy protein isolate (SP), and two blends (Blend 1 and Blend 2) consisting of ratios of 50:25:25 and 25:50:25 for whey:caseinate:soy, respectively, were evaluated for their ability to affect MPS. Methods Male Sprague-Dawley rats were trained to eat 3 meals/day: a 4 g meal at 0700-0720 hr followed by ad lib feeding at 1300-1400 hr and 1800-1900 hr. After ~5 days of training, fasted rats were administered their respective 4 g meal at 0700-0720 hr and an intravenous flooding dose of 2H5-phenylalanine 10 min prior to euthanasia. Individual rats were euthanized at designated postprandial time points. Blood and gastrocnemius samples were collected and the latter was used to measure mixed muscle protein fractional synthetic rates (FSR). Results Plasma leucine concentrations peaked in all groups at 90 min and were still above baseline at 300 min post-meal. FSR tended to increase in all groups post-meal but initial peaks of FSR were different times (45, 90 and 135 minutes for WP or SP, Blend 1 and Blend 2, respectively). Blend 2 had a significantly higher FSR compared to WP alone at 135 minutes (P<0.05). Conclusions Single source proteins and protein blends all enhance skeletal MPS after a meal, however, Blend 2 had a delayed FSR peak which was significantly higher than whey protein at 135 minutes.

The gene expression profile in response to dietary docosahexaenoic acid rich oil for 6 wk was analyzed in the livers of male Sprague-Dawley rats to identify genes whose expression was regulated by dietary modification and correlated with serum lipid changes. Such genes may represent targets for intervention into cardiovascular health using nutraceuticals. High density glass microarrays containing approximately 7800 cloned expressed sequences from rat were used to identify those genes that responded to dietary long chain (n-3) fatty acids. In general, dietary long chain (n-3) fatty acids exhibited statistically significant lipid-lowering effects similar to a pharmaceutical alternative, fenofibrate, but showed narrower effects on the transcription of most of the genes assayed. The transcription patterns confirmed that the expression of several key genes involved in cholesterol metabolism, fatty acid beta-oxidation and lipogenesis was affected. These analyses indicated that stearoyl-coenzyme A (Delta9) desaturase, a key enzyme involved in the regulation of triglyceride biosynthesis and secretion, is a potential target for nutritional intervention for hyperlipidemia and cardiovascular health. In addition these results suggested that regulation of the farnesoid X receptor may be a key nutritionally regulated mediator of serum lipid changes. A nutritional product concept based on a convenient dietary aid demonstrated comparable efficacy with less spurious gene regulation than a pharmaceutical alternative.

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