Exquisite control of cholesterol synthesis is crucial for maintaining homeostasis of this vital yet potentially toxic lipid. Squalene monooxygenase (SM) catalyzes the first oxygenation step in cholesterol synthesis, acting on squalene before cyclization into the basic steroid structure. Using model cell systems, we found that cholesterol caused the accumulation of the substrate squalene, suggesting that SM may serve as a flux-controlling enzyme beyond 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR, considered as rate limiting). Cholesterol accelerated the proteasomal degradation of SM which required the N-terminal domain, partially conserved in vertebrates but not in lower organisms. Unlike HMGR, SM degradation is not mediated by Insig, 24,25-dihydrolanosterol, or side-chain oxysterols, but rather by cholesterol itself. Importantly, SM's N-terminal domain conferred cholesterol-regulated turnover on heterologous fusion proteins. Furthermore, proteasomal inhibition almost totally eliminated squalene accumulation, highlighting the importance of this degradation mechanism for the control of SM and suggesting this as a possible control point in cholesterol synthesis.
Starch provides a large proportion of the dietary energy consumed worldwide. The breakdown of dietary starch is driven by α-amylase produced by the salivary glands and pancreatic acini and is completed by a range of brushborder bound enzymes. This enzymatic digestion is aided by mechanical and secretory actions of the gastrointestinal tract. The absorption of the resultant glucose in the small intestine is primarily driven by two separate transport proteins À SGLT1 and GLUT2. The control of processes that govern starch digestion is complex and still not fully understood, although it appears that the human gut has the ability to sense both glucose and non-sweet glucose oligomers. Recent work has also suggested that variations in the genes encoding for α-amylase also appear to be associated with health outcomes. The authors consider the physiological factors that govern starch digestion and absorption, consider other dietary factors that may impact on this process and attempt to highlight the limitations in current knowledge to help focus future research needs in relation to starch digestion the upper gastrointestinal tract.
It is currently unclear how the process of fat digestion occurs in the mouth of humans. This pilot study therefore aimed to quantify the levels of lipolytic activity at different sites of the mouth and in whole saliva. Samples of whole saliva and from 4 discrete sites in the oral cavity were collected from 42 healthy adult participants. All samples were analyzed for lipolytic activity using two different substrates (olive oil and the synthetic 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6’-methylresorufin) ester (DGGR)). Bland–Altman analyses suggested that the two assays gave divergent results, with 91% and 23% of site-specific and 40% and 26% of whole-saliva samples testing positive for lipolytic activity, respectively. Non-parametric multiple comparisons tests highlighted that median (IQR) of lipolytic activity (tested using the olive oil assay) of the samples from the parotid 20.7 (11.7–31.0) and sublingual 18.4 (10.6–47.2) sites were significantly higher than that of whole saliva 0.0 (0.0–35.7). In conclusion, lipolysis appears to occur in the oral cavity of a proportion of individuals. These findings give a preliminary indication that lipolytic agent activity in the oral cavity may be substrate-specific but do not discount that the enzyme is from sources other than oral secretions (e.g., microbes, gastric reflux).
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