▪ Abstract The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps that accomplish this transformation also confer detergent properties to the bile acid, which are exploited by the body to facilitate the secretion of cholesterol from the liver. This role in the elimination of cholesterol is counterbalanced by the ability of bile acids to solubilize dietary cholesterol and essential nutrients and to promote their delivery to the liver. The synthesis of a full complement of bile acids requires 17 enzymes. The expression of selected enzymes in the pathway is tightly regulated by nuclear hormone receptors and other transcription factors, which ensure a constant supply of bile acids in an ever changing metabolic environment. Inherited mutations that impair bile acid synth...

The Enzymes, Regulation, and Genetics of Bile Acid Synthesis

Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and ...

Oxysterols: modulators of cholesterol metabolism and other processes.

Cholesterol balance is maintained by a series of regulatory pathways that control the acquisition of cholesterol from endogenous and exogenous sources and the elimination of cholesterol, facilitated by its conversion to bile acids. Over the past decade, investigators have discovered that a family of membrane-bound transcription factors, sterol regulatory element-binding proteins (SREBPs), mediate the end-product repression of key enzymes of cholesterol biosynthesis. Recently orphan members of another family of transcription factors, the nuclear hormone receptors, have been found to regulate key pathways in bile acid metabolism, thereby controlling cholesterol elimination. The study of these orphan nuclear receptors suggests their potential as targets for new drug therapies.

The role of orphan nuclear receptors in the regulation of cholesterol homeostasis

A molecular model of human branched-chain amino acid metabolism.

Targeted Deletion of the Ileal Bile Acid Transporter Eliminates Enterohepatic Cycling of Bile Acids in Mice

In this study, hepatic production of bile acid was considered together with intestinal cholesterol absorption as potential regulatory sites responsive to dietary cholesterol. Sequential liver biopsies were taken from 45 feral African green monkeys studied during three different diet periods. Low-fat Monkey Chow was fed during the baseline period, a cholesterol and fat-enriched diet was then fed for 12 wk during period 2, and finally, after a washout period of 10 wk, three subgroups were fed low-, moderate-, and high-cholesterol diets for 12 mo during period 3. The percentage of cholesterol absorbed in the intestine was significantly lower when higher levels of cholesterol were fed; however, this percentage was significantly and positively correlated to plasma cholesterol concentration at each dietary cholesterol level. Hepatic free and esterified cholesterol content were significantly elevated by dietary cholesterol challenge and remained elevated even after 20 wk of low-cholesterol diets. Hepatic mRNA abundance for cholesterol 7 alpha-hydroxylase (C7H) was significantly lower (approximately 60%) when the high-cholesterol diet was fed, with the decrease being greater than that seen for low density lipoprotein (LDL) receptor mRNA. At the same time, hepatic mRNA abundance for apolipoprotein B and hepatic lipase were not diet sensitive. C7H activity was decreased to a similar extent by diet as was C7H mRNA, although the correlation between enzyme activity and mRNA abundance was only r = 0.5, suggesting that dietary regulation includes factors in addition to transcriptional regulation. Activity and mRNA abundance of C7H remained decreased when liver esterified cholesterol content was reduced to only a two- to three-fold elevation over baseline, at a time when plasma cholesterol and hepatic LDL receptor mRNA abundance had returned to baseline levels. These data on liver C7H, obtained in one of the few primate species predisposed to cholesterol gallstone formation, support the hypothesis that the liver may attempt to downregulate intestinal cholesterol absorption by decreasing bile acid production when increased amounts of absorbed dietary cholesterol reach the liver. Presumably this represents attempted downregulation of intestinal cholesterol absorption by limiting bile acid availability as a means to maintain hepatic cholesterol balance.

/pdf/dietary-cholesterol-and-downregulation-of-cholesterol-7-3z02khjejh.pdf

Dietary cholesterol and downregulation of cholesterol 7 alpha-hydroxylase and cholesterol absorption in African green monkeys.

Background: Alzheimer’s disease and related dementias (ADRD) patients who are hospitalized often develop oropharyngeal dysphagia, increasing risk for adverse outcomes, such as aspiration pneumonia. However, prevalence estimates of dysphagia are highly variable and often based on patient report or clinical testing rather than visualization of the swallow. Objective: The aims of this study were to determine prevalence and severity of dysphagia among inpatients with ADRD referred for swallowing evaluation. Methods: Electronic health record (EHR) abstraction of ADRD diagnosis and presence and severity of clinically-determined dysphagia on bedside swallow evaluation (BSE) and videofluoroscopic swallow study (VFSS). Results: 16% (n = 268) had an ADRD diagnosis or were taking dementia-specific medication based on the EHR. 75% (n = 202) were diagnosed with dysphagia on the BSE. 60% subsequently underwent VFSS (n = 122) with dysphagia confirmation in 92% (n = 112). ADRD inpatients were significantly more likely to be diagnosed with dysphagia based on the BSE (p < 0.0001) than those without ADRD. Additionally, dysphagia on the VFSS was more severe in the ADRD group (p < 0.03). Discussion: ADRD individuals may be vulnerable to developing or worsening dysphagia during hospitalization. Results underscore the importance of evaluating swallowing function in hospitalized patients with ADRD in order to facilitate targeted intervention.

https://content.iospress.com/download/journal-of-alzheimers-disease/jad220402?id=journal-of-alzheimers-disease/jad220402

Dysphagia Profiles Among Inpatients with Dementia Referred for Swallow Evaluation

Purpose: The purpose of this study was to examine the difference of two laryngeal closure transition measures: initiation of laryngeal closure (ILC) and laryngeal closure duration (LCD) among stroke survivors, head and neck cancer survivors, and healthy age-matched controls.Methods: ILC and LCD were determined by analyzing two 5ml thin liquid swallows exhibited by each of the 15 stroke survivors, 15 head and neck cancer survivors, and 15 healthy controls from the videofluoroscopic swallowing examinations (VFSEs). Statistical analyses were made using one-way analysis of variance (ANOVA) using the three groups as independent variables with the statistical level set at p<0.05.Results: ILC was longer in stroke survivors compared to head and neck survivors and healthy controls; however, these results were only significant compared to controls. Head and neck cancer survivors exhibited significantly longer LCD when compared to healthy controls, but not to stroke survivors.Conclusions: Differential diagnosis based on swallowing pathophysiology is critical to manage and treat dysphagia in these populations.

Differences of laryngeal closure during the swallow between stroke and head and neck cancer survivors

Management of Dysphagia in Neurodegenerative Disease

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Dietary cholesterol and downregulation of cholesterol 7 alpha-hydroxylase and cholesterol absorption in African green monkeys.

Dysphagia Profiles Among Inpatients with Dementia Referred for Swallow Evaluation

Differences of laryngeal closure during the swallow between stroke and head and neck cancer survivors

Management of Dysphagia in Neurodegenerative Disease