Hepatic Output Research Articles

Severe body condition loss lowers hepatic output of IGF1 with adverse effects on the dominant follicle in dairy cows

The severe loss of body condition score (BCS) during the early lactation period has been associated with infertility in cows. However, the mechanisms are not fully understood. The aim of this study was to examine the effect of BCS loss on liver health, and ovarian functions in cows during early lactation. Retrospectively multiparous cows from two farms were categorized based on units of BCS (1–5 scale) loss as Moderate (MOD, <0.75 units; n = 11) or Severe (SEV, ≥0.75 units; n = 9) loss groups. From Weeks −3 to 7, relative to calving, MOD and SEV cows lost on average 0.4 and 1.0-unit BCS, respectively. All data except hepatic transcriptomes were analyzed with PROC MIXED procedure of SAS. The plasma concentration of non-esterified fatty acids at Week 0 and 1, ß-hydroxy butyrate at Week 1, and γ-glutamyl transferase at Weeks 1 and 7 relative to calving were higher in SEV cows. Hepatic transcriptome analysis showed that 1 186 genes were differentially expressed in SEV (n = 3) compared to MOD (n = 3) cows at Week 7 after calving. Pathway analysis revealed that significant DEGs in SEV cows enriched in lipid metabolisms including, lipid metabolic process, ether lipid metabolism, fatty acid beta-oxidation, fatty acid biosynthetic process, fatty acid metabolic process, fat digestion and absorption, linoleic acid metabolism, alpha-linolenic acid metabolism. The impaired liver function in SEV cows was associated with 1.5-fold reduction of hepatic IGF1 gene expression and lower serum IGF1 concentrations. At the ovarian level, SEV cows had lower IGF1 concentration in the follicular fluid of the dominant follicle of the synchronized follicular wave compared to that of MOD cows at 7 weeks after calving. Further, the follicular fluid concentration of estradiol-17β was lower in SEV cows along with lower transcript abundance of genes from granulosa cells associated with dominant follicle competence, including CYP19A1, NR5A2, IGF1, and LHCGR. These data show that SEV loss of BCS during early lactation leading up to the planned start of breeding is associated with liver dysfunction, including lower IGF1 secretion, and impaired function of the dominant follicle in the ovary.

β-Hydroxybutyrate Oxidation Is Reduced and Hepatic Balance of Ketone Bodies and Free Fatty Acids Is Unaltered in Carnitine-Depleted, Pivalate-Treated Rats

These experiments were designed to determine whether carnitine depletion in the rat due to pivalate administration causes reduced β-hydroxybutyrate oxidation and alterations in hepatic balance of ketone bodies and free fatty acids, relative to control rats. Male rats were given 20 mmol/L sodium pivalate for 2 wk to induce a secondary carnitine deficiency. Control animals were given 20 mmol/L sodium bicarbonate in their drinking water. In the ketone utilization experiment, rats were food-deprived for 24 h and infused with the sodium salt of β-hydroxybutyrate to maintain total plasma ketone concentrations between 6.0 and 10.0 mmol/L. After a bolus of 3-hydroxy[3-14C]butyrate, the recovery of expired 14CO2 collected during the ensuing 100 main was significantly lower in the pivalate-treated rats than in the controls (P < 0.05). In the second experiment, blood samples from pivalate-treated and control rats were collected from the abdominal aorta, portal vein and hepatic vein to determine the hepatic balance (hepatic input — hepatic output) of ketone bodies and free fatty acids. No significant differences were seen between the two treatment groups for either ketone bodies or free fatty acids. We conclude that the higher plasma ketone concentrations seen in food-deprived, pivalate-treated rats were due to a lower rate of ketone utilization. No evidence of pivalate influence upon ketone production was found.

FRI116 - Change in hepatic output of palmitic acid after weight loss in type 2 diabetes

FRI116 - Change in hepatic output of palmitic acid after weight loss in type 2 diabetes

1845-P: Divergent Effects on T2D of Alleles Associated with Increased Liver Fat Reflect Differential Impact on Hepatic Glucose and Lipid Output: An IMI DIRECT Study

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) often coincide but the physiological relationship is unclear. Important clues are provided by human genetics: variants associated with NAFLD-risk have divergent effects on T2D. At TM6SF2 the NAFLD-risk allele (rs58542926:T) predisposes to T2D whilst at GCKR (rs1260326:T), it protects. We hypothesize that these divergent effects result from the impact of NAFLD-raising alleles on hepatic lipid output (HLO) and hepatic glucose output (HGO) respectively. To test this hypothesis, we applied structural equation modeling (SEM) to data from the IMI-DIRECT study, including 1350 European participants, 923 nondiabetic (C1) and 427 with recently-diagnosed T2D (C2). Insulin sensitivity (IS) was modeled from frequently sampled OGTT (C1) and mixed-meal tolerance tests (C2), and liver fat (LF) measured by MRI. SEM fit was assessed by comparing model χ2s with comparable null models: variables randomized to nodes in identical SEM definition giving comparable degrees of freedom and structure, 10,000 iterations. The hypothesized model provided a better fit than null models (C1: χ2=242, P=0.005; C2: χ2=63, P=0.01). Decreasing HLO (via TM6SF2) was associated with an increase in LF (C1: ß=0.28 [SE 0.09], P=0.001; C2: ß=0.28 [0.12], P=0.02) and fasting plasma glucose (FG): these were mediated by LF and IS (C1: ß=0.09 [0.03], P=0.001; C2: ß=0.07 [0.03], P=0.027). Decreasing HGO (via GCKR) was not associated with LF in either cohort but was associated with a direct (non-mediated) decrease in FG (C1 only: ß=-0.08 [0.04], P=0.04). The results support a model whereby increased genetic risk of NAFLD, arising from defects in two processes (HLO and HGO) results in opposing glycemic effects. This has important consequences for therapeutic strategies for combatting NAFLD: approaches to reduce NAFLD through targeting of HLO (as opposed to HGO) may also reduce risk of hyperglycaemia and T2D. Disclosure R.W. Koivula: None. P.W. Franks: Board Member; Self; Zoe Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Novo Nordisk Foundation, Sanofi, Servier. T.H. Hansen: None. M. Laakso: None. E. Pearson: None. F. Rutters: None. F. Karpe: None. J.W. Tomlinson: Advisory Panel; Self; Novo Nordisk Inc., Pfizer Inc., Poxel SA. A. Mahajan: None. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck &amp; Co., Inc. Consultant; Spouse/Partner; Merck &amp; Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Funding Novo Nordisk Foundation (NNF18OC0031650); Innovative Medicines Initiative Joint Undertaking (115317)

Perturbed Whole-body Vitamin a Kinetics Induced by Iron Deficiency Is Corrected by Dietary Iron Repletion in Rats (OR05-03-19)

ObjectivesWe investigated the impact of iron repletion on vitamin A (VA) metabolism and kinetics in iron-deficient rats, hypothesizing that iron repletion can remove the inhibitory effect of iron deficiency on hepatic mobilization of VA and improve the hyporetinolemia of iron deficiency. MethodsAt weaning, rats were divided into two groups and fed either a VA-marginal diet (control group, CN) with normal levels of iron (37 ppm) or the same diet with reduced iron (5 ppm, iron deficient group, ID-). After 5 weeks, n = 4 rats from each group were euthanized for baseline measurements, and the remaining rats (n = 6 CN, n = 10 ID-) received an i.v. dose of 3H-labeled retinol in an emulsion as tracer to initiate the kinetic study. On day 21 after dosing, half of the ID- rats were switched to the CN diet, thus creating an iron repletion group (ID+). Serial blood samples were collected from each rat at 34 preselected time points after dosing. On day 92, all rats were euthanized. Iron and VA status were determined, and model-based compartmental analysis was applied to the plasma tracer data to develop VA kinetic models for rats from all groups. ResultsRats fed the iron-deficient diet developed iron deficiency, and exhibited reduced plasma retinol (0.67 vs. 1.19 μmol/L), with higher liver VA (265 vs. 187 nmol) at the start of the kinetic study, suggesting impaired hepatic VA mobilization. At the study conclusion, ID+ rats had recovered from iron deficiency, as indicated by hematological indices including hemoglobin, hematocrit, and serum iron. While liver VA storage was more than doubled in ID- rats (456 nmol) vs. CN rats (190 nmol), hyporetinolemia was maintained in ID- rats. In contrast, VA in the liver of ID+ rats was mobilized, reflected by the reduced liver VA mass (276 nmol) and increased hepatic output of VA into plasma based on predictions of the compartmental model, and plasma retinol in ID + rats returned to normal. ConclusionsIron repletion restored plasma retinol concentrations and increased liver vitamin A mobilization in iron deficient rats. Funding SourcesNational Institutes of Health.

Neural Modulation of Liver Function to Regulate Lipid and Glucose Metabolism

Mammalian blood glucose concentrations are maintained within well‐defined biological limits despite considerable fluctuations in the rate at which glucose is obtained from food and utilized by tissues. Of all homeostatic mechanisms, maintenance of blood glucose levels is finely regulated, and one in which the liver and the central nervous system play a prominent role. The liver can add or remove glucose from circulating blood in accordance with the demands of the body, which are transmitted by both hormonal and neural messaging. The hormonal messaging system is well understood, unlike the neural messaging system. Hormonal messaging is mediated by the pancreatic hormones insulin and glucagon, which have opposite effects on blood glucose levels. In contrast, the neural messaging system is controlled via two pathways innervating the liver ‐ one sympathetic and one parasympathetic, both originating from hypothalamic areas. Previous studies have shown that electrical stimulation of these hypothalamic nuclei can lead to rapid changes in blood glucose levels. Additional studies have also shown that electrical stimulation of peripheral nerves innervating the liver can lead to changes in hepatic output, however the limitations associated with neural control of glucose and lipid levels is unclear. Here we take an interdisciplinary approach to characterizing the use of electrical stimulation to control hepatic glucose and lipid metabolism. Using electrical stimulation, we demonstrate and characterize the ability to modulate both sympathetic and parasympathetic activity to the liver, enabling modulation of the glucose clearance rate assessed via oral glucose tolerances tests. Furthermore, we demonstrate how electrical stimulation can modulate lipid metabolism as a function of frequency, amplitude, and location of stimulation.Support or Funding InformationThis work is funded by the GlaxoSmithKline Bioelectronics Initiative.

Surgical technology catheterization hepatic arteri under selective intra-arterial chemotherapy

Developed and introduced into clinical practice methods of hepatic artery catheterization through the right gastro-omental artery and (or) the right gastric artery, which let you quickly and without risk of bleeding catheter set for different types of blood supply to the liver for selective intraarterial chemotherapy. After catheterization of hepatic artery own output stump artery with a catheter through a tunnel formed in the round ligament of the liver in kontraperturny puncture in the right upper quadrant and left in this state for the whole period of treatment, or set subcutaneous arterial port. Method angiostomy allow transport of anticancer drugs directly to the target organ, and on the other hand delimit the prepared arterial vessel from the free abdominal cavity. Selective intra-arterial chemotherapy on the described method was performed in 326 patients with liver metastases from colorectal cancer. During or after treatment, complications occurred in 17 patients, accounting for 5.2%. In determining the extent of reactions NCI toxicity scale was used. The proposed method of treatment allows for selective intraarterial combination chemotherapy in patients with different variants of the blood supply to the liver. It is advisable in all cases produce a block lymphadenectomy gate liver exposing the structures of the celiac trunk and cholecystectomy. The proposed sequence of actions in the performance of selective intra-arterial chemotherapy can simultaneously take into account the anatomical variations, as well as to avoid possible mistakes and complications.

Trans fatty acid retention and conversion rates of fatty acids in tissues depend on dietary fat in mice

Given that the effects of trans fatty acids (TFA) may be associated with the type of TFA isomer and the proportion of n‐3/n‐6/n‐9 fatty acids (FA), this work aimed to investigate the influence of different oils on the following parameters: content, incorporation, and retention of TFA; conversion of vaccenic acid (VA) to rumenic acid (RA) in different tissues; and hepatic output of TFA by VLDL. Another objective was to assess relative conversion rates of key FA and the potential alteration of FA composition induced by TFA in tissues. Male CF1 mice were fed (30‐days) diets containing 7% olive, corn or rapeseed oils either supplemented with 0.75% of TFA or without added TFA. FA composition of liver, epididymal adipose tissue, gastrocnemius muscle, brain, and serum was assessed. With the exception of the brain, TFAs were incorporated into the analyzed tissues and serum. TFA retention and RA bioconversion from VA depended on the dietary unsaturated FA proportions. The higher levels of hepatic RA in the liver of mice fed an olive oil+TFA diet could be associated with a raised Δ9‐desaturase index. The FA composition of tissues was scarcely modified by the consumption of partially hydrogenated vegetable oils containing similar proportions of t9‐, t10‐, and t11‐18:1.Practical applications: The present study evaluates the interaction of hydrogenated vegetable oils with different edible oils and the impact on the FA profile and, specifically, TFA incorporation and retention in the tissues. Since the characterization of FA present in tissues might be determining the biological effects of edible fats, this study is relevant for elucidation of existing controversial findings associated with the intake of TFA and its effects on human metabolic alterations.The levels of trans fatty acids (TFA) in a particular tissue might be related to different variables including: type and level of the dietary TFA isomer; uptake, metabolization and release from the tissue, and interference with different dietary fatty acids.

Sex related differences on valproic acid pharmacokinetics after oral single dose

Plasma concentration-time data obtained after an oral single dose of 500-mg valproic acid (VPA) in a delayed release formulation was used to model enterohepatic cycling of the drug. Fourteen healthy subjects (seven women and seven men) were enrolled, food intake was standardized, blood samples were withdrawn up to 48h post dosing and VPA plasma concentrations were analyzed by HPLC-UV method. Secondary peaks of VPA were observed in almost all subjects. A population pharmacokinetic analysis with sex, weight, age and contraceptive therapy as possible covariates was performed. Women without contraceptive therapy presented a longer lag time, a lower VPA hepatic output and a higher reabsorbed fraction than men. Weight affected both volume of the central compartment and the absorption rate constant. Women under contraceptive therapy showed similar disposition parameters to men. Reabsorbed fraction of bioavailable dose was 46.2% in women and 21.8% in men, revealing important sex differences in drug hepatobiliar output. These results showed that VPA displays sex-related pharmacokinetic differences due to different metabolic and transporter-mediated disposition.

Different Contribution of Splanchnic Organs to Hyperlactatemia in Fecal Peritonitis and Cardiac Tamponade

Background. Changes in hepatosplanchnic lactate exchange are likely to contribute to hyperlactatemia in sepsis. We hypothesized that septic and cardiogenic shock have different effects on hepatosplanchnic lactate exchange and its contribution to hyperlactatemia. Materials and Methods. 24 anesthetized pigs were randomized to fecal peritonitis (P), cardiac tamponade (CT), and to controls (n = 8 per group). Oxygen transport and lactate exchange were calculated during 24 hours. Results. While hepatic lactate influx increased in P and in CT, hepatic lactate uptake remained unchanged in P and decreased in CT. Hepatic lactate efflux contributed 20% (P) and 33% (CT), respectively, to whole body venous efflux. Despite maintained hepatic arterial blood flow, hepatic oxygen extraction did not increase in CT. Conclusions. Whole body venous lactate efflux is of similar magnitude in hyperdynamic sepsis and in cardiogenic shock. Although jejunal mucosal pCO2 gradients are increased, enhanced lactate production from other tissues is more relevant to the increased arterial lactate. Nevertheless, the liver fails to increase hepatic lactate extraction in response to rising hepatic lactate influx, despite maintained hepatic oxygen consumption. In cardiac tamponade, regional, extrasplanchnic lactate production is accompanied by hepatic failure to increase oxygen extraction and net hepatic lactate output, despite maintained hepatic arterial perfusion.

Bevacizumab in Patients With Hereditary Hemorrhagic Telangiectasia and Severe Hepatic Vascular Malformations and High Cardiac Output

Bevacizumab in Patients With Hereditary Hemorrhagic Telangiectasia and Severe Hepatic Vascular Malformations and High Cardiac Output

Abstract 16: ApoA5 Reduces Atherosclerosis in LDL Receptor-Deficient Mice

Apolipoprotein A5 (ApoA5) is a lipid-binding protein that is associated mainly with high-density lipoprotein (HDL) and to a lesser extent with very low-density lipoprotein (VLDL). ApoA5 gene variants are linked to altered lipid metabolism and increased risk of cardiovascular disease in humans. To investigate the role of ApoA5 in lipid metabolism, we placed transgenic mice expressing human ApoA5 and age/sex-matched control littermates on high fat diet for 20 weeks. We show that transgenic production of human ApoA5 resulted in significant improvement in hepatic and plasma lipid metabolism, protecting against the development of dyslipidemia and fatty liver disease in high fat-fed mice. To address the underlying mechanism, we determined hepatic triglyceride production vs. systemic triglyceride clearance. ApoA5 transgenic mice, as opposed to control littermates, exhibited significantly reduced hepatic output and enhanced clearance of triglyceride-rich particles. Furthermore, we show that purified ApoA5 proteins were capable of stimulating lipoprotein lipase (LPL) activity, contributing to accelerated VLDL-TG hydrolysis in a cell-free system. To determine the potential beneficial effect of ApoA5 on atherogenesis, we crossed the human ApoA5 transgene into LDL receptor knockout (LDLR-/-) mice. We demonstrate that transgenic ApoA5 production resulted in significant reduction in plasma lipid levels in LDLR -/- mice on high fat and high cholesterol diet. This effect translated into a significant reduction in atherosclerotic lesion in the aortic root of LDLR -/- mice. From our studies we conclude: 1) ApoA5 acts to inhibit hepatic lipogenesis and limit hepatic VLDL-TG output, 2) ApoA5 augments LPL activity and enhances the systemic clearance of TG-rich particles, and 3) ApoA5 possesses anti-atherogenic property, protecting against the development of atherosclerosis in LDLR -/- mice.

Glycemic Control in the Intensive Care Unit and during the Postoperative Period

Glycemic Control in the Intensive Care Unit and during the Postoperative Period

Beyond LDL Cholesterol, a New Role for PCSK9

Elevated low-density lipoprotein cholesterol (LDLC) levels in the plasma is the most important causative factor of atherosclerosis and associated ischemic cardiovascular diseases. The LDL receptor (LDLR) is the preferential pathway through which LDLs are cleared from the circulation. LDLs bound to the LDLR are internalized into clathrin-coated pits and subsequently undergo lysosomal degradation, whereas the LDLR is recycled back to the plasma membrane. See accompanying article on page 1333 Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with elevated LDL levels and premature coronary heart disease. FH is caused primarily by mutations of the LDLR or of apolipoprotein B100 (apoB100), the protein component of LDL that interacts with the LDLR. In 2003, “gain of function” mutations on a newly identified gene, proprotein convertase subtilisin/kexin type 9 ( PCSK9), were associated with FH. In 2005, a causative association was established between “loss of function” mutations in PCSK9 and low LDLC levels in 2% of the African-American population. The coronary heart disease risk in these individuals was reduced by 88%. As a result of these landmark studies (reviewed in Reference 1), PCSK9 became the subject of intensive research to discover the underlying mechanisms. PCSK9 is a serine protease mainly expressed in the liver and the intestine. It acts by reducing the amount of LDLR in hepatocytes. This was demonstrated in vitro and in mouse models …

Changes in hepatic blood flow during whole body hyperthermia

Purpose: Changes in blood flow distribution are important for heat dispersion and for supportive therapeutic strategies such as simultaneous whole body hyperthermia (WBH) and administration of chemotherapy. The aim of this clinical study was to determine changes in hepatic blood flow during WBH for the treatment of metastatic cancer.Materials and methods: This observational clinical study was part of a phase I/II feasibility study of WBH. WBH was induced using a radiant heat device. Hepatic blood flow was estimated using indocyanine green clearance measurements. The plasma disappearance rate of indocyanine green (PDR-ICG) was recorded in percent/min. We used an invasive thermo-dye-dilution technique to estimate hepatic blood flow, cardiac output, and volume status. Mean arterial blood pressure was also measured invasively. To determine the effects of hyperthermia the measurements were performed at defined temperature points.Results: In 10 of 22 treatments the PDR-ICG fell below normal values during hyperthermia, which represented a significant fall in hepatic blood flow. Cardiac output, volume status, and mean arterial blood pressure did not differ between patients whose liver blood flow was reduced and those whose liver blood flow remained unchanged.Conclusions: We observed distinct reductions in hepatic blood flow during WBH, which suggested a significant redistribution of blood flow away from the core during WBH. This was not mirrored by global circulatory parameters.

Effects of ruminal protein degradability and frequency of supplementation on nitrogen retention, apparent digestibility, and nutrient flux across visceral tissues in lambs fed low-quality forage1

Two experiments were conducted to determine the effect of ruminal protein degradability and supplementation frequency on intake, apparent digestibility, N retention, and nutrient flux across visceral tissues of lambs fed a low-quality forage diet. In both experiments, wethers were fed a basal diet of mature crested wheatgrass hay (4.2% CP) for ad libitum consumption plus 1 of 4 supplements: 1) a high RDP supplement provided daily (RDP-D), 2) the high RDP supplement provided on alternate days (RDP-A), 3) a high RUP provided on alternate days (RUP-A), or 4) a 50:50 mixture of the RDP and RUP supplements provided on alternate days. In Exp. 1, 12 lambs (29.9 +/- 2.7 kg initial BW) were used. Forage OM, NDF, and ADF intake were not affected by treatment. Total tract digestibilities (OM, NDF, ADF, and N) were unaffected (P >or= 0.15) by treatment. Neither protein degradability nor supplementation frequency had an effect (P >or= 0.52) on N retention. In Exp. 2, 15 lambs (34 +/- 4 kg initial BW) fitted with indwelling catheters in a hepatic vein, the hepatic portal vein, a mesenteric vein, and a mesenteric artery were used. Release of ammonia N by the portal-drained viscera (PDV) was reduced (P = 0.004) in alternate-day-supplemented lambs compared with RDP-D. Consequently, hepatic uptake of ammonia N was least (P = 0.003) in all alternate-day lambs. Alpha-amino nitrogen (AAN) release by the PDV and hepatic uptake of AAN were not affected by treatment or supplementation frequency. Additionally, hepatic output and PDV uptake of urea N were not affected by treatment. Hepatic N uptake (ammonia N + AAN) accounted for urea synthesized by the liver in all treatments; however, hepatic urea synthesis was approximately 4.5-fold less for RUP-A lambs. This suggests that the provision of AA as RUP may provide a delay in ureagenesis, thus altering the timing of N recycling.

Abstract 5476: Hepatic Over-Expression of Cholesteryl Ester Hydrolase Enhances Cholesterol Elimination and in vivo Reverse Cholesterol Transport

Neutral Cholesteryl ester hydrolase (CEH) mediated hydrolysis of cellular cholesteryl esters (CE) is required not only to generate free cholesterol for efflux from macrophages but also to release FC from lipoprotein delivered CE in the liver for bile acid synthesis or direct secretion into the bile. We hypothesized that hepatic expression of CEH will regulate the hydrolysis of lipoprotein derived CE and enhance reverse cholesterol transport (RCT). Adenoviral mediated CEH over-expression led to a significant increase (&gt;3 fold) in bile acid output (see Figure ). To assess the role of hepatic CEH in promoting flux of cholesterol from macrophages to feces, cholesterol loaded and [ 3 H]-cholesterol labeled J774 macrophages were injected intraperitoneally into mice and appearance of [ 3 H]-cholesterol in gall bladder bile and feces over 48 hours was quantified. Mice over-expressing CEH had significantly higher [ 3 H]-cholesterol in bile and feces and it was associated with bile acids. This CEH-mediated increased movement of [ 3 H]-cholesterol from macrophages to bile and feces was significantly attenuated in SR-BI−/−mice. These studies demonstrate that similar to macrophage CEH that rate limits the first step, hepatic CEH regulates the last step of RCT by promoting the flux of cholesterol entering the liver via SR-BI and increasing hepatic bile acid output. This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia &amp; Washington, DC).

A New Twist in the Cholesterol Metabolism-Based Enterohepatic Connection

A New Twist in the Cholesterol Metabolism-Based Enterohepatic Connection

CETP expression enhances liver HDL-cholesteryl ester uptake but does not alter VLDL and biliary lipid secretion

The aim of this work was to study how CETP expression affects whole body cholesterol homeostasis. Thus, tissue uptake and plasma removal rates of labeled HDL-cholesteryl ester (CE), VLDL secretion rates, and biliary lipid secretion and fecal bile acid content were compared between human CETP transgenic (Tg) and non-transgenic (nTg) mice fed with a standard diet. CETP Tg mice exhibited increased HDL-CE plasma fractional catabolic rate and uptake by the liver, adrenals, adipose tissue and spleen. HDL fractions from both CETP Tg and from nTg mice were removed faster from the plasma of CETP expressing than from nTg mice, suggesting a direct role of CETP in accelerating tissue CE uptake. However, neither hepatic output of VLDL cholesterol and triglycerides nor biliary lipid and fecal bile acid excretion were changed in CETP Tg compared to nTg mice. CETP Tg mice also showed enhanced hepatic cholesterol content. Steady state cholesterol homeostasis was probably preserved through the downregulation of hepatic HMG-CoA reductase and LDL receptor expression. In conclusion, although CETP expression facilitates cholesteryl ester tissue uptake, it does not alter biliary lipid and fecal bile acid excretion, the mandatory final step of the reverse cholesterol transport.

Fasting Induces Hyperlipidemia in Mice Overexpressing Proprotein Convertase Subtilisin Kexin Type 9: Lack of Modulation of Very-Low-Density Lipoprotein Hepatic Output by the Low-Density Lipoprotein Receptor

Several proprotein convertase subtilisin kexin type 9 (PCSK9) mutations lead to familial hypercholesterolemia by virtue of its role as a negative modulator of the low-density lipoprotein receptor (LDLr). Here, we uncover that upon dietary challenge, the down-regulation of the LDLr is also a key mechanism by which PCSK9 modulates the hepatic production of apolipoprotein-B-containing lipoproteins. Thus, adenoviral-mediated overexpression of PCSK9 in 24-h fasted mice results in massive hyperlipidemia, due to a striking increase in very-low-density lipoprotein (VLDL) triglycerides and apolipoprotein B100 hepatic output. Similar studies in LDLr (-/-) mice demonstrate that PCSK9-mediated alteration of VLDL output in the fasted state requires the LDLr. This increased production of VLDL was associated with a concomitant reduction of intrahepatic lipid stores as well as a lack of down-regulation of peroxisome proliferator-activated receptor-alpha activity and target genes expression. Finally, we show that PCSK9 hepatic expression is inhibited by the hypotriglyceridemic peroxisome proliferator-activated receptor-alpha agonist fenofibrate. In summary, the negative modulation of LDLr expression by PCSK9, which decreases plasma LDL clearance, also promotes an overproduction of nascent VLDL in vivo upon fasting.