Overview of bile acid signaling in the cardiovascular system

Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.     

Digestion and absorption

Carbohydrates are digested by salivary and pancreatic amylases to di-, tri- and oligosaccharides, and then to monosaccharides by enzymes on the wall of the small intestine to allow them to be absorbed. Proteins are absorbed as amino acids and small peptides that are broken down to amino acids within the cells. Monosaccharides and amino acids pass into the liver via the portal vein. Fats are digested and absorbed as free fatty acids and glycerides that are then mostly reconstituted as triglycerides in the mucosal cells of the small intestine. They combine with phospholipids and a protein to form chylomicrons, which pass via the lymphatics and the thoracic duct into the systemic circulation. Fatty acids are re-esterified and stored as triglycerides in adipose tissue or oxidized for energy. Water is passively absorbed due to the osmotic gradient that results mainly due to the active absorption of sodium ions.     

Measurement of serum branched-chain amino acids to tyrosine ratio level is useful in a prediction of a change of serum albumin level in chronic liver disease.

Aim: In patients with hepatitis C virus (HCV)-associated chronic liver diseases, especially in those with liver cirrhosis, accurate evaluation of their protein nutrition status is very important to improve their quality of life. Whereas the serum albumin level is commonly used to evaluate patients' protein nutrition status, in the present study, the serum amino acid levels were measured, as they also provide valuable information. Methods: Serum albumin levels and branched-chain amino acids (BCAA) to tyrosine ratio (BTR) were determined in 447 patients with HCV-associated chronic liver diseases (313 with chronic hepatitis and 134 with liver cirrhosis). Results: Chronic hepatitis progressed to liver cirrhosis, serum albumin and serum BTR levels decreased significantlyas chronic hepatitis progressed to liver cirrhosis. Hypoalbuminemia was significantly more common in patients with liver cirrhosis than in those with chronic hepatitis; however, the incidence of an amino acid imbalance was significantly higher than that of hypoalbuminemia in patients with liver cirrhosis. The presence of an amino acid imbalance was associated with a reduction in the serum albumin level 1 year later. Conclusions: It is important to evaluate serum albumin levels and the BTR in patients with HCV-associated chronic liver diseases.     

Cardiac function and ischaemic tolerance during acute loss of metabolic control in the diabetic BB Wor rat

Abstract The effect of loss of metabolic control, by with-holding insulin treatment, on reperfusion recovery of cardiac function following ischaemia was studied in the spontaneously diabetic “BB” Wor rat. The study involved a group of insulin-treated diabetic BB rats (insulin-treated) and diabetic BB rats in which insulin treatment was withheld 24 h prior to study (insulin-withdrawn). Hearts were isolated and perfused at a constant left atrial filling pressure of 15 cm H₂O and aortic afterload resistances of 100 and 140 cm H₂O. Hearts were then subjected to 20 min of ischaemia followed by 30 min of reperfusion. Withdrawing insulin treatment from the BB Wor rat resulted in a dramatic increase in the levels of plasma glucose and free fatty acids. Hearts from these rats perfused under aerobic conditions demonstrated reductions in heart rate, positive and negative dP/dt, cardiac output and left ventricular minute work, whereas diastolic pressure was elevated. Following ischaemia, recovery of cardiac function in the insulin-treated BB Wor rat returned to preischaemic levels, whereas hearts from insulin-withdrawn rats displayed impaired recovery. Throughout reperfusion, heart rate, positive dP/dt, cardiac output and left ventricular minute work remained significantly lower in hearts from insulin-withdrawn rats compared to treated rats. Our results indicate that acute loss of metabolic control increases the sensitivity of the heart to ischaemia, even in the acutely diabetic BB Wor rat.     

Effects of exogenous hormones and glucose on plasma levels and hepatic metabolism of amino acids in the fetus and in the newborn rat

Summary The present study examines the role of insulin, glucagon and cortisol in the regulation of gluconeogenesis from lactate and amino acids in fetal and newborn rats. Injection of glucagon in the fullterm fetal rat caused a rise in glucose (and insulin) and a fall in blood levels of most individual amino acids, stimulated hepatic accumulation of ¹⁴C-amino isobutyric acid and ¹⁴C-cycloleucine and increased the conversion of ¹⁴C lactate, alanine and serine to glucose in vivo and in vitro (liver slices). Such changes were equivalent to the changes seen in 4 h old newborn rats. When glucagon was administered at birth, little difference was observed between control and treated animals in plasma amino acids and a smaller increment in conversion of ¹⁴C substrate to glucose occurred. By contrast, insulin injection at birth caused hypoglycemia, suppression of levels of certain amino acids and inhibition of conversion of ¹⁴C substrates into glucose. Glucose injection at birth caused elevated glycemia and plasma insulin and suppression of most amino acid levels and of conversion of ¹⁴C substrate into glucose. Cortisol injection at birth caused a marked, generalized hyperaminoacidemia, a stimulation of glucagon secretion and of conversion of ¹⁴C substrates into glucose. These observations support the thesis that glucagon plays a major role in the induction of hepatic gluconeogenesis and that insulin acts as an antagonist hormone.     

Effects of partial ileocolectomy and Crohn's disease on biliary lipid secretion

The effects of interruption of the enterohepatic circulation of bile acids on biliary lipid secretion have only been studied experimentally, and quantitative data in patients are lacking. Therefore, biliary lipid secretion during steady-state meal perfusion of the duodenum was studied in six patients with partial ileocolectomy, five patients with Crohn's disease, and five normal subjects. Bile acid outputs in the resection patients were significantly lower than in normal controls, (6.87±2.10 mmol/6 hr and 13.5±2.16, respectively;P<0.001) and were also decreased in two of the five Crohn's disease patients. Bile acid outputs in patients with resection progressively decreased in the course of the perfusion study; phospholipid and cholesterol secretion did not decrease to the same extent, and cholesterol saturation gradually increased. Bile of these patients, therefore, was frequently supersaturated due to uncoupling of bile acid secretion and outputs of the other biliary lipids. Bile acid outputs, although decreased, did not reach very low values, which shows that the enterohepatic circulation was not totally interrupted. Chenodeoxycholic acid was the main bile acid component of bile in patients with ileocolonic resection. Deoxycholic acid was absent from bile of four resected patients and two Crohn's patients. Two patients with active Crohn's disease had low bile acid outputs despite only moderate fecal bile acid losses. Therefore, decreased outputs may be caused by decreased bile acid pool not compensated for by increased bile acid synthesis in severely ill patients.     

Effect of intravenous omeprazole on intragastric pH during intravenous infusion of amino acids

Intravenous amino acids stimulate gastric acid secretion by an unknown mechanism. In patients on parenteral nutrition, this amino acid-induced gastric acid secretion might contribute to the failure of H₂-receptor antagonists to raise intragastric pH above 4.0, a level thought to be needed to prevent stress ulceration. Therefore we studied the effect of single and repeated doses of the H⁺/K⁺-ATPase blocker omeprazole on the intragastric pH during a 3-hr infusion of amino acids in 10 healthy volunteers; 5% glucose was used as a control infusion. Amino acids significantly decreased intragastric pH when compared to glucose infusion (P <0.05). After intravenous administration of 40 mg, 80 mg and 2 × 40 mg omeprazole, this amino acid-induced fall in pH was significantly inhibited (P < 0.01). No advantage of the 80-mg dose over the 40-mg dose could be demonstrated. The repeated dose of 40 mg showed a tendency to higher pH values compared to the single-dose experiments, which reached significance in the amino acid experiments only (P <0.05). Neither during the infusion of amino acids nor the glucose infusion omeprazole was able to continuously raise intragastric pH above 4.0. In conclusion, this study shows that intravenous omeprazole prevents gastric acid stimulation by intravenous amino acids but fails to continuously raise intragastric pH above 4.     

Possible roles of insulin,glucagon, growth hormone and free fatty acids in the pathogenesis of insulin resistance of subjects with chronic liver diseases

Summary In the present investigation, insulin sensitivity and fasting levels of insulin, C-peptide, glucagon, growth hormone and free fatty acids were estimated and correlated in a population of individuals suffering from liver cirrhosis or chronic hepatitis. Insulin sensitivity, assessed by glucose disappearance rate after intravenous bolus injection of insulin, was reduced but not significantly different from controls in subjects with chronic persistent hepatitis, while it was significantly reduced in individuals suffering from chronic active hepatitis or liver cirrhosis. Insulin, glucagon, growth hormone, and free fatty acid fasting levels were higher than in healthy subjects in individuals with liver cirrhosis or chronic active hepatitis but not in subjects with chronic persistent hepatitis. C-peptide concentrations did not differ from controls in subjects with liver disease. Significant negative correlations occurred between coefficients of insulin sensitivity and fasting concentrations of insulin, glucagon, growth hormone and free fatty acids, but not with fasting levels of C-peptide. Positive relationships were present between fasting levels of free fatty acids and both glucagon and growth hormone concentrations. These results show that, unlike subjects with liver cirrhosis and chronic active hepatitis, individuals suffering from chronic persistent hepatitis do not differ from healthy subjects in insulin sensitivity and fasting levels of insulin, glucagon, growth hormone, and free fatty acids. Moreover, they suggest that both hyperinsulinemia and high concentrations of counterregulatory substances might play a role in the pathogenesis of insulin resistance in subjects suffering from chronic liver disease. Supported by grants from the Ministry of Public Education and grant No. 83/02132.04 from the National Research Council (C.N.R.), Rome.     

Gut‐derived short‐chain fatty acids: A friend or foe for hepatic lipid metabolism?

This article describes how a British Nutrition Foundation Drummond Pump Priming Award was used to develop in vivo proof of concept for increasing colonic propionate as a therapeutic strategy to reduce liver fat in adults with non‐alcoholic fatty disease (NAFLD). An overview of how the gut‐derived short‐chain fatty acids propionate and acetate are taken up and metabolised by the liver is provided, as well as a summary of how acetate may have contrasting effects on hepatic lipid content depending on the metabolic health of the individual. Finally, the article proposes that raising colonic propionate production could interfere with hepatic acetate metabolism and have positive effects on liver fat accumulation in individuals with NAFLD.     

Improving pulse crops as a source of protein,starch and micronutrients

Pulse crops have been known for a long time to have beneficial nutritional profiles for human diets but have been neglected in terms of cultivation, consumption and scientific research in many parts of the world. Broad dietary shifts will be required if anthropogenic climate change is to be mitigated in the future, and pulse crops should be an important component of this change by providing an environmentally sustainable source of protein, resistant starch and micronutrients. Further enhancement of the nutritional composition of pulse crops could benefit human health, helping to alleviate micronutrient deficiencies and reduce risk of chronic diseases such as type 2 diabetes. This paper reviews current knowledge regarding the nutritional content of pea (Pisum sativum L.) and faba bean (Vicia faba L.), two major UK pulse crops, and discusses the potential for their genetic improvement.