Enhanced conversion of dietary cholesterol to bile acids through the alternative pathway leads to... more Enhanced conversion of dietary cholesterol to bile acids through the alternative pathway leads to cold-associated, metabolically beneficial changes in the intestinal microbiome and to elevated bile acid levels that contribute to adaptive thermogenesis.
American Journal of Physiology-gastrointestinal and Liver Physiology, Mar 1, 1993
We have compared the effects of bilirubin and bilirubin ditaurate (BDT) on biliary phospholipid a... more We have compared the effects of bilirubin and bilirubin ditaurate (BDT) on biliary phospholipid and cholesterol secretion in unanesthetized normal Wistar (NW) and Groningen Yellow (GY) Wistar rats under various experimental conditions. GY rats express a genetic defect in biliary secretion, but not in hepatic uptake, of various organic anions. Under physiological conditions, NW and GY rats showed similar biliary secretion rates of bile acids and of bilirubin, despite the fact that bilirubin concentrations in GY plasma were 25 times as high and in GY livers three times as high as in NW plasma and livers, respectively. Secretion of cholesterol and phospholipids was not impaired in GY rats under these conditions. Biliary secretion of intravenously injected BDT (3 mumol/100 g body wt) was delayed in eight-day bile-diverted GY rats and showed lower peak values when compared with NW rats. The inhibitory effects of BDT on phospholipid and cholesterol secretion paralleled these differences, being delayed and much less pronounced in GY rats. No overshoot in phospholipid or cholesterol secretion was observed when bilirubin output returned to preinjection values. Stimulation of [14C]choline-labeled phospholipid secretion after a bolus injection of taurochenodeoxycholic acid (1 mumol/100 g body wt) closely followed biliary bile acid concentration. Similarly, inhibition of labeled phospholipid secretion by BDT closely paralleled the biliary bilirubin concentration. Gel filtration studies (Sepharose 4B-CL) under micelle-preserving conditions demonstrated a specific interaction of BDT with biliary bile acids. The presented data indicate that conjugated bilirubin does not inhibit biliary lipid secretion via interaction with bile acids inside the hepatocyte.(ABSTRACT TRUNCATED AT 250 WORDS)
Disturbed cholesterol homeostasis is associated with multiple diseases, such as atherosclerotic c... more Disturbed cholesterol homeostasis is associated with multiple diseases, such as atherosclerotic cardiovascular disease, lysosomal storage disorders, and neurodegenerative disorders. The endo-lysosomal network plays a central role in the distribution of cholesterol between subcellular membranes, but the processes controlling this transport are still not well-defined. Here, we investigate the impact of hepatic Retromer, an endosomal sorting complex consisting of VPS35, VPS26, and VPS29, on cholesterol homeostasis by using a liver-specific VPS35-deficient (Vps35HepKO) mouse model. Hepatic VPS35 deficiency strongly reduces the function of the lysosomal proteins lysosomal acid lipase (LAL), scavenger receptor class B member 2 (SCARB2), and Niemann-Pick type C1 (NPC1), concomitant with hepatic cholesterol accumulation in lysosomal compartments, delayed transport of endocytosed cholesterol through the endo-lysosomal network, and increased cholesterol biosynthesis. In addition, the levels a...
The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) ... more The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) are involved in the regulation of multiple biological processes, including lipid metabolism and inflammation. The activation of these receptors has been found to have neuroprotective effects, making them interesting therapeutic targets for neurodegenerative disorders such as Alzheimer’s Disease (AD). The Asian brown seaweed Sargassum fusiforme contains both LXR-activating (oxy)phytosterols and PPAR-activating fatty acids. We have previously shown that dietary supplementation with lipid extracts of Sargassum fusiforme prevents disease progression in a mouse model of AD, without inducing adverse effects associated with synthetic pan-LXR agonists. We now determined the LXRα/β- and PPARα/γ-activating capacity of lipid extracts of six European brown seaweed species (Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, Himanthalia elongata, Saccharina latissima, and Sargassum muticum) and...
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Cyp2c70-/- mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acid... more Cyp2c70-/- mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acids (MCAs), have been reported to display cholangiopathy and biliary fibrosis with female preponderance that can be reversed by ursodeoxycholic acid (UDCA). Obeticholic acid (OCA), a steroidal BA-like FXR agonist, has been shown to improve liver function in patients with primary biliary cholangitis and is approved as second-line treatment for patients with an inadequate response or intolerance to UDCA. Here, we investigated the impact of OCA on BA hydrophobicity and cholangiopathy in Cyp2c70-/- mice. Male and female wild-type (WT) and Cyp2c70-/- mice were fed a chow diet with or without 10 mg/kg/day OCA for 4 weeks. OCA accounted for 1-5% of biliary BAs, with larger enrichments in Cyp2c70-/- than in WT mice. In WT mice, OCA induced a more hydrophilic, MCA-rich BA pool. In Cyp2c70-/- mice, however, BA pool became more hydrophobic with a larger proportion of chenodeoxycholic acid, attributable to a reduction of BA 12α-hydroxylation. OCA treatment reduced fecal BA excretion, indicating repression of hepatic BA synthesis in both WT and Cyp2c70-/- mice. OCA did, however, not impact on markers of liver (dys)function in plasma nor did it ameliorate cholangiopathy and fibrosis in male or female Cyp2c70-/- mice. OCA treatment also did not affect the expression of genes involved in fibrosis, inflammation and cellular senescence. In conclusion, 4 weeks of OCA treatment oppositely modulates the hydrophobicity of the BA pool in WT and Cyp2c70-/- mice, but does not improve or worsen the characteristic sex-dependent liver pathology in Cyp2c70-/- mice.
Journal of Pediatric Gastroenterology and Nutrition, 2019
Objectives and study: The mouse is a frequently used species in experimental models for human dis... more Objectives and study: The mouse is a frequently used species in experimental models for human diseases. By using inbred mice under controlled conditions, the genetic and environmental variations are supposedly minimized. Recently, however, we discovered serendipitously a spontaneous bimodal variation in liver size in a frequently used mouse strain (C57BL/6JOlaHsd). We now determined if the spontaneous variation in liver weight is translated to metabolic differences with respect to bile acid (BA) homeostasis and Very Low Density Lipoprotein (VLDL) secretion. Methods: We fed male wildtype C57BL/6JOlaHsd mice a commonly used standardized semi-synthetic diet (AIN-93G) from birth to 10 weeks of age. We determined plasma BA concentration and composition, by LC-MS/MS, and VLDL secretion, for 5h after intraperitoneal injection of a lipoprotein lipase inhibitor (poloxamer-407). In separate mice, we measured fasting plasma lipids and hepatic mRNA expression of relevant genes. Values represent...
Enhanced conversion of dietary cholesterol to bile acids through the alternative pathway leads to... more Enhanced conversion of dietary cholesterol to bile acids through the alternative pathway leads to cold-associated, metabolically beneficial changes in the intestinal microbiome and to elevated bile acid levels that contribute to adaptive thermogenesis.
American Journal of Physiology-gastrointestinal and Liver Physiology, Mar 1, 1993
We have compared the effects of bilirubin and bilirubin ditaurate (BDT) on biliary phospholipid a... more We have compared the effects of bilirubin and bilirubin ditaurate (BDT) on biliary phospholipid and cholesterol secretion in unanesthetized normal Wistar (NW) and Groningen Yellow (GY) Wistar rats under various experimental conditions. GY rats express a genetic defect in biliary secretion, but not in hepatic uptake, of various organic anions. Under physiological conditions, NW and GY rats showed similar biliary secretion rates of bile acids and of bilirubin, despite the fact that bilirubin concentrations in GY plasma were 25 times as high and in GY livers three times as high as in NW plasma and livers, respectively. Secretion of cholesterol and phospholipids was not impaired in GY rats under these conditions. Biliary secretion of intravenously injected BDT (3 mumol/100 g body wt) was delayed in eight-day bile-diverted GY rats and showed lower peak values when compared with NW rats. The inhibitory effects of BDT on phospholipid and cholesterol secretion paralleled these differences, being delayed and much less pronounced in GY rats. No overshoot in phospholipid or cholesterol secretion was observed when bilirubin output returned to preinjection values. Stimulation of [14C]choline-labeled phospholipid secretion after a bolus injection of taurochenodeoxycholic acid (1 mumol/100 g body wt) closely followed biliary bile acid concentration. Similarly, inhibition of labeled phospholipid secretion by BDT closely paralleled the biliary bilirubin concentration. Gel filtration studies (Sepharose 4B-CL) under micelle-preserving conditions demonstrated a specific interaction of BDT with biliary bile acids. The presented data indicate that conjugated bilirubin does not inhibit biliary lipid secretion via interaction with bile acids inside the hepatocyte.(ABSTRACT TRUNCATED AT 250 WORDS)
Disturbed cholesterol homeostasis is associated with multiple diseases, such as atherosclerotic c... more Disturbed cholesterol homeostasis is associated with multiple diseases, such as atherosclerotic cardiovascular disease, lysosomal storage disorders, and neurodegenerative disorders. The endo-lysosomal network plays a central role in the distribution of cholesterol between subcellular membranes, but the processes controlling this transport are still not well-defined. Here, we investigate the impact of hepatic Retromer, an endosomal sorting complex consisting of VPS35, VPS26, and VPS29, on cholesterol homeostasis by using a liver-specific VPS35-deficient (Vps35HepKO) mouse model. Hepatic VPS35 deficiency strongly reduces the function of the lysosomal proteins lysosomal acid lipase (LAL), scavenger receptor class B member 2 (SCARB2), and Niemann-Pick type C1 (NPC1), concomitant with hepatic cholesterol accumulation in lysosomal compartments, delayed transport of endocytosed cholesterol through the endo-lysosomal network, and increased cholesterol biosynthesis. In addition, the levels a...
The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) ... more The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) are involved in the regulation of multiple biological processes, including lipid metabolism and inflammation. The activation of these receptors has been found to have neuroprotective effects, making them interesting therapeutic targets for neurodegenerative disorders such as Alzheimer’s Disease (AD). The Asian brown seaweed Sargassum fusiforme contains both LXR-activating (oxy)phytosterols and PPAR-activating fatty acids. We have previously shown that dietary supplementation with lipid extracts of Sargassum fusiforme prevents disease progression in a mouse model of AD, without inducing adverse effects associated with synthetic pan-LXR agonists. We now determined the LXRα/β- and PPARα/γ-activating capacity of lipid extracts of six European brown seaweed species (Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, Himanthalia elongata, Saccharina latissima, and Sargassum muticum) and...
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Cyp2c70-/- mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acid... more Cyp2c70-/- mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acids (MCAs), have been reported to display cholangiopathy and biliary fibrosis with female preponderance that can be reversed by ursodeoxycholic acid (UDCA). Obeticholic acid (OCA), a steroidal BA-like FXR agonist, has been shown to improve liver function in patients with primary biliary cholangitis and is approved as second-line treatment for patients with an inadequate response or intolerance to UDCA. Here, we investigated the impact of OCA on BA hydrophobicity and cholangiopathy in Cyp2c70-/- mice. Male and female wild-type (WT) and Cyp2c70-/- mice were fed a chow diet with or without 10 mg/kg/day OCA for 4 weeks. OCA accounted for 1-5% of biliary BAs, with larger enrichments in Cyp2c70-/- than in WT mice. In WT mice, OCA induced a more hydrophilic, MCA-rich BA pool. In Cyp2c70-/- mice, however, BA pool became more hydrophobic with a larger proportion of chenodeoxycholic acid, attributable to a reduction of BA 12α-hydroxylation. OCA treatment reduced fecal BA excretion, indicating repression of hepatic BA synthesis in both WT and Cyp2c70-/- mice. OCA did, however, not impact on markers of liver (dys)function in plasma nor did it ameliorate cholangiopathy and fibrosis in male or female Cyp2c70-/- mice. OCA treatment also did not affect the expression of genes involved in fibrosis, inflammation and cellular senescence. In conclusion, 4 weeks of OCA treatment oppositely modulates the hydrophobicity of the BA pool in WT and Cyp2c70-/- mice, but does not improve or worsen the characteristic sex-dependent liver pathology in Cyp2c70-/- mice.
Journal of Pediatric Gastroenterology and Nutrition, 2019
Objectives and study: The mouse is a frequently used species in experimental models for human dis... more Objectives and study: The mouse is a frequently used species in experimental models for human diseases. By using inbred mice under controlled conditions, the genetic and environmental variations are supposedly minimized. Recently, however, we discovered serendipitously a spontaneous bimodal variation in liver size in a frequently used mouse strain (C57BL/6JOlaHsd). We now determined if the spontaneous variation in liver weight is translated to metabolic differences with respect to bile acid (BA) homeostasis and Very Low Density Lipoprotein (VLDL) secretion. Methods: We fed male wildtype C57BL/6JOlaHsd mice a commonly used standardized semi-synthetic diet (AIN-93G) from birth to 10 weeks of age. We determined plasma BA concentration and composition, by LC-MS/MS, and VLDL secretion, for 5h after intraperitoneal injection of a lipoprotein lipase inhibitor (poloxamer-407). In separate mice, we measured fasting plasma lipids and hepatic mRNA expression of relevant genes. Values represent...
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