Plasma Phosphatidylcholine Alterations in Cystic Fibrosis Patients: Impaired Metabolism and Correlation with Lung Function and Inflammation

Background: Liver impairment, ranging from steatosis to cirrhosis, is frequent in cystic fibrosis (CF) patients and is becoming increasingly significant due to their improved life expectancy. One aspect of hepatic alterations is caused by increased fecal loss of the essential nutrient choline, following enterohepatic bile phosphatidylcholine (PC) cycle impairment. Hepatic PC synthesis, both de novo and via phosphatidylethanolamine-N-methyl-transferase (PEMT), is essential for very low-density lipoprotein (VLDL) secretion. VLDL-PC in particular contributes to the organism's supply with polyunsaturated fatty acids (LC-PUFA), namely arachidonic (C20:4) and docosahexaenoic acid (C22:6). Consequently, choline deprivation and altered hepatic PC metabolism may affect plasma PC homeostasis and extrahepatic organ function. Objectives: To investigate relationships between altered plasma choline and PC homeostasis and markers of lung function and inflammation in CF. To assess alterations in hepatic choline and PC metabolism of CF patients. Design: Quantification of plasma/serum choline and PC species in adult CF patients compared to controls. Correlation of PC with forced expiratory vital capacity (FEV1) and interleukin 6 (IL-6) concentrations. Analysis of choline and PC metabolism in CF compared to controls, using deuterated choline ([D9-methyl]-choline) labeling in vivo. Results: Mean choline and PC concentrations in CF patients were lower than in controls. Choline and PC concentrations as well as fractions of C22:6-PC and C20:4-PC correlated directly with FEV1, but inversely with IL-6. Plasma concentrations of deuterated PC were decreased for both pathways, whereas only in PC synthesized via PEMT precursor enrichment was decreased. Conclusion: In CF patients, hepatic and plasma homeostasis of choline and PC correlate with lung function and inflammation. Impaired hepatic PC metabolism, exemplarily shown in three CF patients, provides an explanation for such correlations. Larger studies are required to understand the link between hepatic PC metabolism and overall clinical performance of CF patients, and the perspective of choline substitution of these patients.

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Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans

PLoS Genetics ◽

10.1371/journal.pgen.1009891 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1009891

Author(s):

Baocai Xie ◽

Xiaochen Shi ◽

Yan Li ◽

Bo Xia ◽

Jia Zhou ◽

...

Keyword(s):

Cardiovascular Disease ◽

De Novo ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Atherogenic Diet ◽

Standard Diet ◽

Low Levels ◽

Reduced Risk

Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.

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The Effect of Fructose Feeding on Intestinal Triacylglycerol Production and De Novo Fatty Acid Synthesis in Humans

Nutrients ◽

10.3390/nu12061781 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1781

Author(s):

Simon Steenson ◽

Fariba Shojaee-Moradie ◽

Martin B. Whyte ◽

Kim G. Jackson ◽

Julie A. Lovegrove ◽

...

Keyword(s):

De Novo ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Acute Effect ◽

De Novo Lipogenesis ◽

Fructose Intake ◽

High Fructose ◽

Catabolic Rate

A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 h. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (p < 0.005) and VLDL-TAG (p = 0.003) were greater, and CM-TAG production rate (PR, p = 0.046) and CM-TAG fractional catabolic rate (FCR, p = 0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (p = 0.005) and apoB48 (p = 0.039), apoB100 (p = 0.013) and non-esterified fatty acids (NEFA) (p = 0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (p = 0.043) and low-fructose (p = 0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase.

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Inhibition of cholesterogenesis decreases hepatic secretion of apoB-100 in normolipidemic subjects.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.3.e462 ◽

1997 ◽

Vol 273 (3) ◽

pp. E462 ◽

Cited By ~ 2

Author(s):

G F Watts ◽

R P Naoumova ◽

J M Kelly ◽

F M Riches ◽

K D Croft ◽

...

Keyword(s):

De Novo ◽

Low Density Lipoprotein ◽

Plasma Concentrations ◽

Density Lipoprotein ◽

Mevalonic Acid ◽

Normal Subjects ◽

Gas Chromatography Mass Spectrometry ◽

Low Density ◽

Cholesterol Ratio ◽

Kinetics Of

We examined the effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the kinetics of very low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in 13 normolipidemic men in a placebo-controlled crossover study. Simvastatin significantly decreased the plasma concentrations of low-density lipoprotein (LDL) cholesterol by 36%, triglycerides by 26%, mevalonic acid by 34%, and lathosterol by 32%. Hepatic secretion of VLDL apoB was measured using a primed constant intravenous infusion of [1-13C]leucine with monitoring of isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional turnover rate was derived using a monoexponential function. Simvastatin decreased VLDL apoB pool size by 53% and the hepatic secretion rate of VLDL apoB by 46% but did not significantly alter its fractional catabolism. The change in hepatic VLDL apoB secretion was significantly and independently correlated with changes in plasma mevalonic acid and lathosterol concentrations and the lathosterol-to-cholesterol ratio. The data support the hypothesis that the rate of de novo cholesterol synthesis directly regulates the hepatic secretion of VLDL apoB in normal subjects.

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Impaired-Inactivation of FoxO1 Contributes to Glucose-Mediated Increases in Serum Very Low-Density Lipoprotein

Endocrinology ◽

10.1210/en.2010-0204 ◽

2010 ◽

Vol 151 (8) ◽

pp. 3566-3576 ◽

Cited By ~ 13

Author(s):

Ke Wu ◽

David Cappel ◽

Melissa Martinez ◽

John M. Stafford

Keyword(s):

Blood Glucose ◽

De Novo ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Serum Triglyceride ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Experimental Conditions ◽

Adenoviral Delivery

For patients with diabetes, insulin resistance and hyperglycemia both contribute to increased serum triglyceride in the form of very low-density lipoprotein (VLDL). Our objective was to define the insulin conditions in which hyperglycemia promotes increased serum VLDL in vivo. We performed hyperglycemic-hyperinsulinemic clamp studies and hyperglycemic-hypoinsulinemic clamp studies in rats, with metabolic tracers for glucose flux and de novo fatty acid synthesis. When blood glucose was clamped at hyperglycemia (17 mm) for 2 h under hyperinsulinemic conditions (4 mU/kg · min), serum VLDL levels were not increased compared with baseline. We speculated that hyperinsulinemia minimized glucose-mediated VLDL changes and performed hyperglycemic-hypoinsulinemic clamp studies in which insulin was clamped near fasting levels with somatostatin (17 mm blood glucose, 0.25 mU/kg · min insulin). Under low-insulin conditions, serum VLDL levels were increased 4.7-fold after hyperglycemia, and forkhead box O1 (FoxO1) was not excluded from the nucleus of liver cells. We tested the extent that impaired inactivation of FoxO1 by insulin was sufficient for glucose to promote increased serum VLDL. We found that, when the ability of insulin to inactivate FoxO1 is blocked after adenoviral delivery of constitutively active FoxO1, glucose increased serum VLDL triglyceride when given both by ip glucose tolerance testing (3.5-fold increase) and by a hyperglycemic clamp (4.6-fold). Under both experimental conditions in which insulin signaling to FoxO1 was impaired, we found increased activation of carbohydrate response element binding protein. These data suggest that glucose more potently promotes increased serum VLDL when insulin action is impaired, with either low insulin levels or disrupted downstream signaling to the transcription factor FoxO1.

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Oxidation of Plasma Low-Density Lipoprotein Accelerates Its Accumulation and Degradation in the Arterial Wall In Vivo

Circulation ◽

10.1161/01.cir.94.7.1698 ◽

1996 ◽

Vol 94 (7) ◽

pp. 1698-1704 ◽

Cited By ~ 46

Author(s):

Klaus Juul ◽

Lars B. Nielsen ◽

Klaus Munkholm ◽

Steen Stender ◽

Børge G. Nordestgaard

Keyword(s):

Arterial Wall ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density

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Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

Biochemical Journal ◽

10.1042/bj2340245 ◽

1986 ◽

Vol 234 (1) ◽

pp. 245-248 ◽

Cited By ~ 31

Author(s):

W Jessup ◽

G Jurgens ◽

J Lang ◽

H Esterbauer ◽

R T Dean

Keyword(s):

Apolipoprotein B ◽

Negative Charge ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Low Density ◽

Lipid Peroxidation Product ◽

Modified Low Density Lipoproteins ◽

Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

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