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.

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.

No abstract

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.