Altered Bile Acid Metabolism in Alloxan Diabetic Rats

Uchida, Keiji; Takase, Haruto; Kadowaki, Masumi; Nomura, Yasuharu; Matsubara, Takashi; Takeuchi, Nozomu

doi:10.1254/jjp.29.553

Cited by 39 publications

(17 citation statements)

References 33 publications

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“…Because biliary BA secretion is a major driving force for biliary cholesterol secretion ( 30 ), cholesterol in T1DM mice. These results are consistent with previously published data demonstrating that alloxanor streptozotocin-induced diabetes increased biliary sterol secretion rates in rats ( 13,28 ). In addition, concentrations Fig.…”

Section: Cyp8b1supporting

confidence: 93%

Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice

Boer

Annema

Schreurs

et al. 2012

Journal of Lipid Research

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Atherosclerotic cardiovascular disease (CVD) is a predominant cause of morbidity and mortality in type 1 diabetes mellitus (T1DM) patients ( 1, 2 ). Compared with subjects without diabetes, T1DM confers a 7-fold increase in the risk of fatal CVD ( 2 ). However, the mechanisms underlying accelerated atherosclerosis in T1DM are still incompletely understood.Plasma HDL cholesterol levels are inversely related to the incidence of CVD ( 3, 4 ). The role of this lipoprotein in promoting reverse cholesterol transport (RCT) is currently regarded as the main established atheroprotective property of HDL ( 5, 6 ). The critical steps in RCT comprise initial effl ux of excess cholesterol from lipid-laden macrophages within atherosclerotic lesions toward HDL for transport through the plasma compartment, followed by the subsequent uptake of cholesterol into the liver for excretion into bile and feces ( 7,8 ).Although T1DM has been associated with changes in sterol metabolism ( 9-13 ), no data are currently available addressing the impact of T1DM on RCT. Therefore, this study explored the pathophysiological consequences of experimental T1DM on overall RCT as well as the individual steps involved in this process. Our data demonstrate that macrophage-specifi c RCT is decreased in T1DM despite increased biliary sterol secretion as well as increased fecal excretion of bile acids (BA s). Mechanistically, we Abstract Type I diabetes mellitus (T1DM) increases atherosclerotic cardiovascular disease; however, the underlying pathophysiology is still incompletely understood. We investigated whether experimental T1DM impacts HDL-mediated reverse cholesterol transport (RCT). C57BL/6J mice with alloxan-induced T1DM had higher plasma cholesterol levels ( P < 0.05), particularly within HDL, and increased hepatic cholesterol content ( P < 0.001). T1DM resulted in increased bile fl ow (2.1-fold; P < 0.05) and biliary secretion of bile acids (BA, 10.5-fold; P < 0.001), phospholipids (4.5-fold; P < 0.001), and cholesterol (5.5-fold; P < 0.05). Hepatic cholesterol synthesis was unaltered, whereas BA synthesis was increased in T1DM ( P < 0.001). Mass fecal BA output was signifi cantly higher in T1DM mice (1.5-fold; P < 0.05), fecal neutral sterol excretion did not change due to increased intestinal cholesterol absorption (2.1-fold; P < 0.05). Overall in vivo macrophage-to-feces RCT, using [ 3 H] cholesterol-loaded primary mouse macrophage foam cells, was 20% lower in T1DM ( P < 0.05), mainly due to reduced tracer excretion within BA ( P < 0.05). In vitro experiments revealed unchanged cholesterol effl ux toward T1DM HDL, whereas scavenger receptor class BI-mediated selective uptake from T1DM HDL was lower in vitro and in vivo (HDL kinetic experiments) ( P < 0.05), conceivably due to increased glycation of HDL-associated proteins (+65%, P < 0.01). In summary, despite higher mass biliary sterol secretion T1DM impairs macrophage-to-feces RCT, mainly by decreasing hepatic selective uptake, a mechanism conceivably contributing to increased cardiovascular...

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Section: Cyp8b1supporting

confidence: 93%

Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice

Boer

Annema

Schreurs

et al. 2012

Journal of Lipid Research

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“…Both rodents (48)(49)(50) and patients ( 51,52 ) with type 1 diabetes show a decrease in cholesterol synthesis. To the extent that this is due to a defect in hepatic cholesterol synthesis, we would expect that the response to statins would be compromised.…”

Section: Discussionmentioning

confidence: 99%

Hepatic insulin receptor deficiency impairs the SREBP-2 response to feeding and statins

Miao

Haas

Manthena

et al. 2014

Journal of Lipid Research

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defects in insulin action: type 1 diabetes is caused by autoimmune-mediated destruction of the ␤ -cells of the pancreas, resulting in insulin defi ciency, whereas type 2 diabetes is caused by insulin resistance and decompensation of the ␤ -cells ( 3 ). Though the most salient action of insulin is to prevent hyperglycemia, the development of CVD and NAFLD are not fully prevented by the normalization of blood glucose levels ( 4 ). Thus, insulin actions on pathways distinct from glucose metabolism may play a role in the development of CVD, NAFLD, and other complications of diabetes.Derangements in cholesterol metabolism are closely associated with atherosclerosis, and could also contribute to the development of NAFLD ( 5 ). Cholesterol biosynthesis and its regulation have therefore been intensively studied over many years ( 6 ). For example, the regulation of cholesterol synthesis by dietary cholesterol has been found to be mediated in large part by the transcription factor sterol regulatory element binding protein (SREBP)-2. SREBP-2 is synthesized as a membrane bound precursor which must undergo proteolytic cleavage to generate its active nuclear form ( 7 ). This cleavage is inhibited by intracellular cholesterol. When intracellular cholesterol levels are low, SREBP-2 increases transcription of the cholesterologenic enzymes and the LDL receptor (LDLR), resulting in increased intracellular cholesterol via a combination of increased cholesterol synthesis and uptake. When cholesterol levels are high, SREBP-2 processing is inhibited, preventing synthesis and uptake of cholesterol. Similarly, statin drugs, which inhibit HMG-CoA reductase (HMGCR) and cholesterol synthesis, are thought to activate SREBP-2 by reducing the amount of cholesterol in the regulatory pool of the cell.

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“…It has long been known that bile acid metabolism is altered in diabetes (18), and the increased levels of circulating bile acids may be partially responsible for increased cholesterol absorption and atherosclerosis in diabetic patients. Insulin is also a potent negative regulator of CYP7A1 in primary hepatocytes (19).…”

Section: Discussionmentioning

confidence: 99%

PGC-1α Activates CYP7A1 and Bile Acid Biosynthesis

Shin

Campos

Gil

et al. 2003

Journal of Biological Chemistry

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Cholesterol 7-␣-hydroxylase (CYP7A1) is the key enzyme that commits cholesterol to the neutral bile acid biosynthesis pathway and is highly regulated. In the current studies, we have uncovered a role for the transcriptional co-activator PGC-1␣ in CYP7A1 gene transcription. PGC-1␣ plays a vital role in adaptive thermogenesis in brown adipose tissue and stimulates genes important to mitochondrial function and oxidative metabolism. It is also involved in the activation of hepatic gluconeogenesic gene expression during fasting. Because the mRNA for CYP7A1 was also induced in mouse liver by fasting, we reasoned that PGC-1␣ might be an important co-activator for CYP7A1. Here we show that PGC-1␣ and CYP7A1 are also co-induced in livers of mice in response to streptozotocin induced diabetes. Additionally, infection of cultured HepG2 cells with a recombinant adenovirus expressing PGC-1␣ directly activates CYP7A1 gene expression and increases bile acid biosynthesis as well. Furthermore, we show that PGC-1␣ activates the CYP7A1 promoter directly in transient transfection assays in cultured cells. Thus, PGC-1␣ is a key activator of CYP7A1 and bile acid biosynthesis and is likely responsible for the fasting and diabetes dependent induction of CYP7A1. PGC-1␣ has already been shown to be a critical activator of several other oxidative processes including adaptive thermogenesis and fatty acid oxidation. Our studies provide further evidence of the fundamental role played by PGC-1␣ in oxidative metabolism and define PGC-1␣ as a link between diabetes and bile acid metabolism. The CYP7A11 enzyme converts cholesterol into 7-␣-hydroxycholesterol, which is the first specific intermediate in the neutral bile acid biosynthesis pathway in the liver (1). This is a crucial enzyme in mammalian cholesterol metabolism as diversion into the bile acid pathway is the main route for eliminating excess cholesterol from the body. Because of its key role in cholesterol metabolism, the CYP7A1 enzyme and its gene have been studied as an important model for dietary regulation for several years. These studies have revealed that there is a significant amount of regulation at the level of transcription initiation (2); however, post-transcriptional mechanisms for control also occur (1, 3).The CYP7A1 promoter has been extensively evaluated by several groups and the proximal regions of both the mouse and rat promoters contain two direct repeat type elements that bind several nuclear receptors, some of which are indicated in Fig. 1. There is also a binding site for the monomeric orphan receptor LRH-1 that overlaps the DR-1 element. The DR-4 is a target site for the nuclear receptor LXR, which confers positive regulation by cholesterol to the CYP7A1 promoter in mice and rats (2). However, the DR-4 is not conserved in the human gene which is not subject to feed forward regulation by cholesterol (4).CYP7A1 is also activated in livers of fasted mice (5). Similarly, the transcriptional co-activator PGC-1␣ is induced by fasting in liver where it activates transcrip...

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Altered Bile Acid Metabolism in Alloxan Diabetic Rats

Cited by 39 publications

References 33 publications

Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice

Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice

Hepatic insulin receptor deficiency impairs the SREBP-2 response to feeding and statins

PGC-1α Activates CYP7A1 and Bile Acid Biosynthesis

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