Abstract:plasma cholesterol levels in NZW rabbits. HypercholesThe effect of bile acid depletion and replacement with terolemia in WHHL rabbits was related to the combinaglycodeoxycholic acid on plasma cholesterol concentration of dysfunctional LDL receptors and inhibited tions, hepatic low-density lipoprotein (LDL) receptor cholesterol 7a-hydroxylase. Plasma cholesterol concenbinding and messenger RNA (mRNA) levels, and hepatic trations were reduced significantly when cholesterol 7a-activities and mRNA levels for 3-hyd… Show more
“…The present study demonstrates that direct augmentation of hepatic 7␣-hydroxylase by gene transfer markedly lowers plasma LDL concentrations even in the absence of LDL receptors. These experimental results are consistent with recent studies showing that interruption of the enterohepatic circulation by ileal bypass or complete biliary diversion significantly lowers plasma LDL cholesterol concentrations in WHHL rabbits lacking functional LDL receptors (34,35). Together, these observations indicate that major reductions in LDL concentrations can be achieved through mechanisms independent of LDL receptor induction.…”
Section: Discussionsupporting
confidence: 92%
“…This study suggests that the modest hypocholesterolemic effect of currently available bile salt sequestrants is related to the limited capacity of these agents to interfere with bile salt absorption and thereby increase hepatic 7␣-hydroxylase activity and bile salt synthesis. More impressive malabsorption of bile salts can be achieved with ileal bypass or complete biliary diversion, and when these procedures are performed in WHHL rabbits, plasma cholesterol concentrations fall by ϳ40% (34,35). However, marked depletion of the enterohepatic bile salt pool is associated with a number of undesirable side effects that make these procedures less than ideal as therapy for clinical hypercholesterolemia (12,40).…”
Section: Fig 7 Effect Of Cholate or Cholestyramine On Hepatic 7␣-hymentioning
This study was undertaken to determine the effect of transient overexpression of hepatic cholesterol 7␣-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptors (LDL receptor ؊/؊). Primary overexpression of hepatic 7␣-hydroxylase in LDL receptor ؊/؊ mice was accompanied by a dosedependent decrease in the rate of LDL cholesterol appearance in plasma (whole body LDL cholesterol transport) and a corresponding reduction in circulating LDL cholesterol levels. The increase in hepatic 7␣-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was ϳ10-fold. In comparison, cholestyramine increased hepatic 7␣-hydroxylase activity ϳ3-fold and reduced plasma LDL cholesterol concentrations by 17%. This study demonstrates that augmentation of hepatic 7␣-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.Conversion of cholesterol to bile salts is the principal regulated pathway whereby cholesterol is removed from the body. The initial and rate-limiting enzyme in the major bile salt biosynthetic pathway is hepatic cholesterol 7␣-hydroxylase (1). Hepatic cholesterol 7␣-hydroxylase is regulated at the transcriptional level in response to bile salts fluxing through the liver in the enterohepatic circulation (2-5). Bile salt sequestrants such as cholestyramine bind bile salts in the intestinal lumen, thereby preventing their reabsorption and decreasing the return of bile salts to the liver. Loss of bile salts from the enterohepatic circulation results in derepression of hepatic 7␣-hydroxylase expression and an increase in the synthesis of bile salts from cholesterol (6 -9). Interventions that accelerate the conversion of cholesterol to bile salts reduce plasma LDL 1 concentrations and prevent coronary events (10 -12). The efficacy of these interventions is postulated to result from a reduction in the availability of unesterified cholesterol within hepatocytes. Depletion of unesterified cholesterol within the hepatocyte triggers a compensatory increase in de novo cholesterol synthesis and induction of the LDL receptor pathway, the latter leading to enhanced clearance of LDL from plasma (7,(13)(14)(15). Although induction of hepatic LDL receptor activity has been emphasized as the major mechanism responsible for the cholesterol-lowering effects of bile salt sequestrants, a recent study suggests that these agents may also reduce the rate of LDL cholesterol entry into plasma (16).Humans (and animals) who genetically lack LDL receptors are characterized by massive elevations of circulating LDL levels, accelerated atherosclerosis, and premature coronary heart disease (17). In the absence of functional LDL receptors, the clearance of LDL from plasma is reduced, and the conversion of VLDL to LDL is increased. In Watanabe heritable hyperlipidemic (WHHL) rabbits, the absence of functional LDL receptors leads to a ϳ20-fold elevation of the plasma LDL concentration that i...
“…The present study demonstrates that direct augmentation of hepatic 7␣-hydroxylase by gene transfer markedly lowers plasma LDL concentrations even in the absence of LDL receptors. These experimental results are consistent with recent studies showing that interruption of the enterohepatic circulation by ileal bypass or complete biliary diversion significantly lowers plasma LDL cholesterol concentrations in WHHL rabbits lacking functional LDL receptors (34,35). Together, these observations indicate that major reductions in LDL concentrations can be achieved through mechanisms independent of LDL receptor induction.…”
Section: Discussionsupporting
confidence: 92%
“…This study suggests that the modest hypocholesterolemic effect of currently available bile salt sequestrants is related to the limited capacity of these agents to interfere with bile salt absorption and thereby increase hepatic 7␣-hydroxylase activity and bile salt synthesis. More impressive malabsorption of bile salts can be achieved with ileal bypass or complete biliary diversion, and when these procedures are performed in WHHL rabbits, plasma cholesterol concentrations fall by ϳ40% (34,35). However, marked depletion of the enterohepatic bile salt pool is associated with a number of undesirable side effects that make these procedures less than ideal as therapy for clinical hypercholesterolemia (12,40).…”
Section: Fig 7 Effect Of Cholate or Cholestyramine On Hepatic 7␣-hymentioning
This study was undertaken to determine the effect of transient overexpression of hepatic cholesterol 7␣-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptors (LDL receptor ؊/؊). Primary overexpression of hepatic 7␣-hydroxylase in LDL receptor ؊/؊ mice was accompanied by a dosedependent decrease in the rate of LDL cholesterol appearance in plasma (whole body LDL cholesterol transport) and a corresponding reduction in circulating LDL cholesterol levels. The increase in hepatic 7␣-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was ϳ10-fold. In comparison, cholestyramine increased hepatic 7␣-hydroxylase activity ϳ3-fold and reduced plasma LDL cholesterol concentrations by 17%. This study demonstrates that augmentation of hepatic 7␣-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.Conversion of cholesterol to bile salts is the principal regulated pathway whereby cholesterol is removed from the body. The initial and rate-limiting enzyme in the major bile salt biosynthetic pathway is hepatic cholesterol 7␣-hydroxylase (1). Hepatic cholesterol 7␣-hydroxylase is regulated at the transcriptional level in response to bile salts fluxing through the liver in the enterohepatic circulation (2-5). Bile salt sequestrants such as cholestyramine bind bile salts in the intestinal lumen, thereby preventing their reabsorption and decreasing the return of bile salts to the liver. Loss of bile salts from the enterohepatic circulation results in derepression of hepatic 7␣-hydroxylase expression and an increase in the synthesis of bile salts from cholesterol (6 -9). Interventions that accelerate the conversion of cholesterol to bile salts reduce plasma LDL 1 concentrations and prevent coronary events (10 -12). The efficacy of these interventions is postulated to result from a reduction in the availability of unesterified cholesterol within hepatocytes. Depletion of unesterified cholesterol within the hepatocyte triggers a compensatory increase in de novo cholesterol synthesis and induction of the LDL receptor pathway, the latter leading to enhanced clearance of LDL from plasma (7,(13)(14)(15). Although induction of hepatic LDL receptor activity has been emphasized as the major mechanism responsible for the cholesterol-lowering effects of bile salt sequestrants, a recent study suggests that these agents may also reduce the rate of LDL cholesterol entry into plasma (16).Humans (and animals) who genetically lack LDL receptors are characterized by massive elevations of circulating LDL levels, accelerated atherosclerosis, and premature coronary heart disease (17). In the absence of functional LDL receptors, the clearance of LDL from plasma is reduced, and the conversion of VLDL to LDL is increased. In Watanabe heritable hyperlipidemic (WHHL) rabbits, the absence of functional LDL receptors leads to a ϳ20-fold elevation of the plasma LDL concentration that i...
“…2), although a modest reduction in WT CA-fed mice was observed (Supplementary Fig. 2), which may be downstream of CYP7A1 repression 27 .Figure 3Cholestasis-induced hepatic dyslipidaemia is attenuated in TRPC5 KO mice. WT and TRPC5 KO mice were fed control (RM3) or CA (0.5% cholic acid supplemented RM3 diet) for 21 days, and ( a ) liver triglyceride (TG), total cholesterol ( b ), and LDL/VLDL ( c ) concentrations were measured.…”
Transient receptor potential canonical 5 (TRPC5), a calcium-permeable, non-selective cation channel is expressed in the periphery, but there is limited knowledge of its regulatory roles in vivo. Endogenous modulators of TRPC5 include a range of phospholipids that have an established role in liver disease, including lysophosphatidylcholine (LPC). Cholestasis is characterized by impairment of excretion of bile acids, leading to elevation of hepatic bile acids. We investigated the contribution of TRPC5 in a murine model of cholestasis. Wild-type (WT) and TRPC5 knock-out (KO) mice were fed a diet supplemented with 0.5% cholic acid (CA) for 21 days. CA-diet supplementation resulted in enlargement of the liver in WT mice, which was ameliorated in TRPC5 KO mice. Hepatic bile acid and lipid content was elevated in WT mice, with a reduction observed in TRPC5 KO mice. Consistently, liver enzymes were significantly increased in cholestatic WT mice and significantly blunted in TRPC5 KO mice. Localized dyslipidaemia, secondary to cholestasis, was investigated utilizing a selected lipid analysis. This revealed significant perturbations in the lipid profile following CA-diet feeding, with increased cholesterol, triglycerides and phospholipids, in WT, but not TRPC5 KO mice. Our results suggest that activation of TRPC5 contributes to the development of cholestasis and associated dyslipidemia. Modulation of TRPC5 activity may present as a novel therapeutic target for liver disease.
“…Sterol 27-hydroxylase activity and mRNA levels are decreased by bile acids in the rat [156] but unaffected in the rabbit [157,158] and mouse [159]. Cholesterol is reported to increase sterol 27-hydroxylase levels in the rabbit [157] but not in the rat [156] or mouse [159]. It has been reported that there is a coordinate regulation of sterol 27-hydroxylase (CYP27A1) and cholesterol 7α-hydroxylase (CYP7A1) by bile acids in rats [160][161][162].…”
Section: Regulationmentioning
confidence: 99%
“…Bile acids and cholesterol appear, however, to affect this enzyme differently in different species. Sterol 27-hydroxylase activity and mRNA levels are decreased by bile acids in the rat [156] but unaffected in the rabbit [157,158] and mouse [159]. Cholesterol is reported to increase sterol 27-hydroxylase levels in the rabbit [157] but not in the rat [156] or mouse [159].…”
This article aims to give an overview on the characterization, properties and regulation of enzymes, particularly the cytochrome (CYP) P450 enzymes, in the formation of bile acids from cholesterol. Bile acids are biologically active molecules that promote absorption of dietary lipids in the intestine and stimulate biliary excretion of cholesterol. Bile acids and oxysterols, formed from cholesterol, act as ligands to nuclear receptors regulating the expression of important genes in cholesterol homeostasis. Thus, the bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The primary human bile acids, cholic acid and chenodeoxycholic acid, are formed from cholesterol via several pathways involving many different enzymes. Many of these enzymes are cytochrome P450 (CYP) enzymes, introducing a hydroxyl group in the molecule. The "classic" pathway of bile acid formation starts with a 7alpha-hydroxylation of cholesterol by CYP7A1 in the liver. The "acidic" pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1. There also exist some quantitatively minor pathways which may be of importance under certain conditions. Formation of cholic acid requires insertion of a 12alpha-hydroxyl group performed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport and are known to affect the expression of several genes in cholesterol homeostasis. Enzymes with capacity to form and metabolize oxysterols are present in liver and extrahepatic tissues. The enzymes, nuclear receptors and transcription factors involved in bile acid biosynthesis are potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and to prevent atherosclerosis and other diseases related to disturbed cholesterol homeostasis. The review will also discuss some inborn errors of bile acid biosynthesis and the recently acquired knowledge on the genetic defects underlying these diseases.
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