A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans.

BACKGROUND AND AIMS: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. APPROACH AND RESULTS: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2-/- mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro . In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. CONCLUSIONS: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases.

Neurobiology of eating behavior, nutrition, and health.

Eating behavior and food-related decision making are among the most complex of the motivated behaviors, and understanding the neurobiology of eating behavior, and its developmental dynamics, is critical to advancing the nutritional sciences and public health. Recent advances from both human and animal studies are revealing that individual capacity to make health-promoting food decisions varies based on biological and physiological variation in the signaling pathways that regulate the homeostatic, hedonic, and executive functions; past developmental exposures and current life-stage; the food environment; and complications of chronic disease that reinforce the obese state. Eating rate drives increased calorie intake and represents an important opportunity to lower rates of food consumption and energy intake through product reformulation. Understanding human eating behaviors and nutrition in the context of neuroscience can strengthen the evidence base from which dietary guidelines are derived and can inform policies, practices, and educational programs in a way that increases the likelihood they are adopted and effective for reducing rates of obesity and other diet-related chronic disease.

Of mice and men: murine bile acids explain species differences in the regulation of bile acid and cholesterol metabolism.

Compared with humans, rodents have higher synthesis of cholesterol and bile acids (BAs) and faster clearance and lower levels of serum LDL-cholesterol. Paradoxically, they increase BA synthesis in response to bile duct ligation (BDL). Another difference is the production of hydrophilic 6-hydroxylated muricholic acids (MCAs), which may antagonize the activation of FXRs, in rodents versus humans. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans. We thus studied the effects of genetic deletion of the Cyp2c70 gene, previously proposed to control MCA formation. Compared with WT animals, KO mice created using the CRISPR/Cas9 system completely lacked MCAs, and displayed >50% reductions in BA and cholesterol synthesis and hepatic LDL receptors, leading to a marked increase in serum LDL-cholesterol. The doubling of BA synthesis following BDL in WT animals was abolished in KO mice, despite extinguished intestinal fibroblast growth factor (Fgf)15 expression in both groups. Accumulation of cholesterol-enriched particles ("Lp-X") in serum was almost eliminated in KO mice. Livers of KO mice were increased 18% in weight, and serum markers of liver function indicated liver damage. The human-like phenotype of BA metabolism in KO mice could not be fully explained by the activation of FXR-mediated changes. In conclusion, the presence of MCAs is critical for many of the known metabolic differences between mice and humans. The Cyp2c70-KO mouse should be useful in studies exploring potential therapeutic targets for human disease.

An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers.

Bile acid (BA) synthesis is regulated through suppression of hepatic cholesterol 7α-hydroxylase via farnesoid X receptor (FXR) activation in hepatocytes and/or enterocytes; in enterocytes, this process requires FGF19 signaling. To study these pathways, we quantified markers of BA synthesis (7α-hydroxy-4-cholesten-3-one [C4]) and cholesterol production (lathosterol), fibroblast growth factor (FGF)19, and BAs in serum from healthy male volunteers given 1 oral dose of the nonsteroidal FXR agonist Px-102 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.12 mg/kg, 2.25 mg/kg, 3.38 mg/kg, or 4.5 mg/kg). After 8 hours, serum levels of C4 decreased by 80% in volunteers given 0.15 mg/kg, whereas serum levels of FGF19 were unchanged. Serum levels of FGF19 increased significantly, in a dose-dependent manner, in volunteers given >0.3 mg/kg Px-102, up to as much as 1600%, whereas C4 levels remained significantly reduced (by >80%). For all doses, FGF19 levels returned to normal 24 hours after administration of Px-102. Serum levels of C4 decreased before levels of FGF19 levels increased, and were still reduced by 95% 24 hours after the highest dose (4.5 mg/kg) of Px-102, even though levels of FGF19 had returned to baseline. Our findings indicate that activation of hepatic FXR is able to suppress BA synthesis, independent of FGF19.

Cholestyramine treatment of healthy humans rapidly induces transient hypertriglyceridemia when treatment is initiated.

Bile acid (BA) production in mice is regulated by hepatic farnesoid X receptors and by intestinal fibroblast growth factor (FGF)-15 (in humans, FGF-19), a suppressor of BA synthesis that also reduces serum triglycerides and glucose. Cholestyramine treatment reduces FGF-19 and induces BA synthesis, whereas plasma triglycerides may increase from unclear reasons. We explored whether FGF-19 may suppress BA synthesis and plasma triglycerides in humans by modulation of FGF-19 levels through long-term cholestyramine treatment at increasing doses. In a second acute experiment, metabolic responses from 1 day of cholestyramine treatment were monitored. Long-term treatment reduced serum FGF-19 by >90%; BA synthesis increased up to 17-fold, whereas serum BAs, triglycerides, glucose, and insulin were stable. After long-term treatment, serum BAs and FGF-19 displayed rebound increases above baseline levels, and BA and cholesterol syntheses normalized after 1 wk without rebound reductions. Acute cholestyramine treatment decreased FGF-19 by 95% overnight and serum BAs by 60%, while BA synthesis increased fourfold and triglycerides doubled. The results support that FGF-19 represses BA synthesis but not serum triglycerides. However, after cessation of both long-term and 1-day cholestyramine treatment, circulating FGF-19 levels were normalized within 2 days, whereas BA synthesis remained significantly induced in both situations, indicating that also other mechanisms than the FGF-19 pathway are responsible for stimulation of BA synthesis elicited by cholestyramine. Several of the responses during cholestyramine treatment persisted at least 6 days after treatment, highlighting the importance of removing such treatment well before evaluating dynamics of the enterohepatic circulation in humans.

High-density lipoprotein-associated sphingosine-1-phosphate activity in heterozygous familial hypercholesterolaemia.

BACKGROUND: Patients with heterozygous familial hypercholesterolaemia (FH) suffer from high plasma cholesterol and an environment of increased oxidative stress. We examined its potential effects on high-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P) content (HDL-S1P) and HDL-mediated protection against oxidative stress, both with and without statin treatment. MATERIALS AND METHODS: In a case-control study, HDL was isolated from 12 FH patients with and without statin treatment and from 12 healthy controls. The HDL-S1P content and the capacity of HDL to protect cardiomyocytes against oxidative stress in vitro were measured. RESULTS: HDL-associated S1P was significantly correlated with cell protection, but not with HDL-cholesterol or apolipoprotein AI. The latter did not correlate with HDL-mediated cell protection. Neither the HDL-S1P content nor HDL protective capacity differed between nontreated FH patients and controls. The relative amounts of apolipoprotein AI and apolipoprotein M were similar between controls and FH patients. Statin treatment had no effect on any of these measures. CONCLUSIONS: The FH environment is not detrimental to HDL-S1P content or HDL-S1P-mediated cell protection. Statin treatment does not modulate HDL function in this regard.

Impaired Cholesterol Efflux Capacity of High-Density Lipoprotein Isolated From Interstitial Fluid in Type 2 Diabetes Mellitus-Brief Report.

OBJECTIVE: Patients with type 2 diabetes mellitus (T2D) have an increased risk of cardiovascular disease, the mechanism of which is incompletely understood. Their high-density lipoprotein (HDL) particles in plasma have been reported to have impaired cholesterol efflux capacity. However, the efflux capacity of HDL from interstitial fluid (IF), the starting point for reverse cholesterol transport, has not been studied. We here investigated the cholesterol efflux capacity of HDL from IF and plasma from T2D patients and healthy controls. APPROACH AND RESULTS: HDL was isolated from IF and peripheral plasma from 35 T2D patients and 35 age- and sex-matched healthy controls. Cholesterol efflux to HDL was determined in vitro, normalized for HDL cholesterol, using cholesterol-loaded macrophages. Efflux capacity of plasma HDL was 10% lower in T2D patients than in healthy controls, in line with previous observations. This difference was much more pronounced for HDL from IF, where efflux capacity was reduced by 28% in T2D. Somewhat surprisingly, the efflux capacity of HDL from IF was lower than that of plasma HDL, by 15% and 32% in controls and T2D patients, respectively. CONCLUSION: These data demonstrate that (1) HDL from IF has a lower cholesterol efflux capacity than plasma HDL and (2) the efflux capacity of HDL from IF is severely impaired in T2D when compared with controls. Because IF comprises the compartment where reverse cholesterol transport is initiated, the marked reduction in cholesterol efflux capacity of IF-HDL from T2D patients may play an important role for their increased risk to develop atherosclerosis.

Levels of atherogenic lipoproteins are unexpectedly reduced in interstitial fluid from type 2 diabetes patients.

At a given level of serum cholesterol, patients with T2D have an increased risk of developing atherosclerosis compared with nondiabetic subjects. We hypothesized that T2D patients have an increased interstitial fluid (IF)-to-serum gradient ratio for LDL, due to leakage over the vascular wall. Therefore, lipoprotein profiles in serum and IF from 35 T2D patients and 35 healthy controls were assayed using fast performance liquid chromatography. The IF-to-serum gradients for VLDL and LDL cholesterol, as well as for apoB, were clearly reduced in T2D patients compared with healthy controls. No such differences were observed for HDL cholesterol. Contrary to our hypothesis, the atherogenic VLDL and LDL particles were not increased in IF from diabetic patients. Instead, they were relatively sparser than in healthy controls. The most probable explanation to our unexpected finding is that these lipoproteins are more susceptible to retainment in the extravascular space of these patients, reflecting a more active uptake by, or adhesion to, tissue cells, including macrophages in the vascular wall. Further studies are warranted to further characterize the mechanisms underlying these observations, which may be highly relevant for the understanding of why the propensity to develop atherosclerosis is increased in T2D.

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol.

Pharmacologically increased estrogen levels have been shown to lower hepatic and plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in animals and humans. We hypothesized that physiological changes in estrogen levels influence circulating PCSK9, thereby contributing to the known wide inter-individual variation in its plasma levels, as well as to the established increase in LDL cholesterol (LDL-C) with normal aging. Circulating PCSK9, estradiol, and other metabolic factors were determined in fasting samples from 206 female and 189 male healthy volunteers (age 20-85 years), The mean levels of PCSK9 were 10% higher in females than in males (P < 0.05). PCSK9 levels were 22% higher in postmenopausal than in premenopausal (P < 0.001) females. Within the group of premenopausal females, circulating PCSK9 correlated inversely to estrogen levels, and PCSK9 was higher (305 ng/ml) in the follicular phase than in the ovulatory (234 ng/ml) or the luteal (252 ng/ml) phases (P < 0.05). Changes in endogenous estrogen levels during the menstrual cycle likely contribute to the broad inter-individual variation in PCSK9 and LDL-C in normal females. PCSK9 levels increase in females after menopause but not in men during this phase in life. This likely contributes to why LDL-C in women increases in this period.

Influence of dietary sugar on cholesterol and bile acid metabolism in the rat: Marked reduction of hepatic Abcg5/8 expression following sucrose ingestion.

Previous studies have indicated that dietary intake of sugar may lower bile acid production, and may promote cholesterol gallstone formation in humans. We studied the influence of dietary sucrose on cholesterol and bile acid metabolism in the rat. In two different experiments, rats received high-sucrose diets. In the first, 60% of the weight of standard rat chow was replaced with sucrose (high-sucrose diet). In the second, rats received a diet either containing 65% sucrose (controlled high-sucrose diet) or 65% complex carbohydrates, in order to keep other dietary components constant. Bile acid synthesis, evaluated by measurements of the serum marker 7-alpha-hydroxy-4-cholesten-3-one (C4) and of the hepatic mRNA expression of Cyp7a1, was markedly reduced by the high-sucrose diet, but not by the controlled high-sucrose diet. Both diets strongly reduced the hepatic - but not the intestinal - mRNA levels of Abcg5 and Abcg8. The differential patterns of regulation of bile acid synthesis induced by the two sucrose-enriched diets indicate that it is not sugar per se in the high-sucrose diet that reduces bile acid synthesis, but rather the reduced content of fiber or fat. In contrast, the marked reduction of hepatic Abcg5/8 observed is an effect of the high sugar content of the diets.

Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome.

BACKGROUND: Liver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. METHODS: We performed a multicentre, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of eprotirome, a liver-selective thyroid hormone receptor agonist, in 98 patients with primary hypercholesterolaemia. After previous drug wash-out and dietary run-in, patients received 100 or 200 µg day(-1) eprotirome or placebo for 12 weeks. The primary end-point was change in serum LDL cholesterol; secondary end-points included changes in other lipid parameters and safety measures. RESULTS: Eprotirome treatment at 100 and 200 µg daily reduced serum LDL cholesterol levels by 23 ± 5% and 31 ± 4%, respectively, compared with 2 ± 6% for placebo (P < 0.0001). Similar reductions were seen in non-HDL cholesterol and apolipoprotein (apo) B, whereas serum levels of HDL cholesterol and apo A-I were unchanged. There were also considerable reductions in serum triglycerides and lipoprotein(a), in particular in patients with elevated levels at baseline. There was no evidence of adverse effects on heart or bone and no changes in serum thyrotropin or triiodothyronine, although the thyroxine level decreased. Low-grade increases in liver enzymes were evident in most patients. CONCLUSION: In hypercholesterolaemic patients, the liver-selective thyromimetic eprotirome decreased serum levels of atherogenic lipoproteins without signs of extra-hepatic side effects. Selective stimulation of hepatic thyroid hormone receptors may be an attractive way to modulate lipid metabolism in hyperlipidaemia.

Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans.

Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome. Both hyperthyroidism and eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect.

Interstitial fluid lipoproteins.

PURPOSE OF REVIEW: The interstitium represents the fluid, proteins, solutes, and extracellular matrix comprising the microenvironment of tissues. We here review attempts to characterize the levels and composition of lipoproteins in human interstitial fluid, and identify potentially important questions for future research. RECENT FINDINGS: Despite the high relevance of understanding how lipoproteins enter and exit the interstitial compartment, and how they interact with extracellular and cellular molecules, scientific progress in this field has been rather slow. This is partly due to methodological difficulties, both regarding how to obtain representative samples and how to perform appropriate measurements to compare patient cohorts and to evaluate responses to treatment. Predominant techniques include peripheral lymph cannulation and suction blister creation, both of which have inherent advantages and disadvantages. Detailed studies comparing the effects of long-term incubation of serum and lymph lipoproteins are compatible with the view that HDL in interstitial fluid takes up free cholesterol from cells and transfers it into the circulation. SUMMARY: Studies of the concentration, composition, functionality, and turnover of interstitial fluid lipoproteins will be of great future interest for understanding how tissue cholesterol metabolism is regulated, and how different diseases link to increased risk for development of atherosclerosis.

Higher prevalence of coronary microvascular dysfunction in asymptomatic individuals with high levels of lipoprotein(a) with and without heterozygous familial hypercholesterolaemia.

BACKGROUND AND AIMS: Microvascular dysfunction underlies many cardiovascular disease conditions; little is known regarding its presence in individuals with high levels of lipoprotein(a) [Lp(a)]. The aim of the present study was to determine the frequency of microvascular dysfunction among such subjects with and without concomitant familial hypercholesterolemia (FH). METHODS: Four groups of asymptomatic individuals aged 30-59 years, without manifest cardiovascular disease, were recruited (n = 30 per group): controls with Lp(a) < 30 nmol/L, mutation-confirmed FH with Lp(a) < 30 nmol/L, or >125 nmol/L, and individuals with isolated Lp(a) > 125 nmol/L. Participants underwent evaluation of myocardial microvascular function by measuring coronary flow reserve (CFR) using transthoracic Doppler echocardiography, and of peripheral microvascular endothelial function by peripheral arterial tonometry. RESULTS: The groups were balanced in age, sex, and body mass index. Each of the three dyslipoproteinaemic groups had a greater proportion of individuals with impaired coronary flow reserve, 30%, compared to 6.7% of controls (p = 0.014). The median CFR levels did not differ significantly between the four groups, however. Cholesterol-lowering treatment time was longer in the individuals with normal than in those with impaired CFR in the FH + Lp(a) > 125 group (p = 0.023), but not in the group with FH + Lp(a) < 30 (p = 0.468). There was no difference in peripheral endothelial function between the groups. CONCLUSIONS: Coronary microvascular dysfunction is more prevalent in asymptomatic individuals with isolated Lp(a) elevation and in heterozygous FH both with and without high Lp(a) compared to healthy controls. Cholesterol-lowering treatment could potentially prevent the development of microvascular dysfunction.

Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia.

BACKGROUND: Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. METHODS: We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either eprotirome (at a dose of 25, 50, or 100 microg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects on the heart, bone, and pituitary. RESULTS: The addition of placebo or eprotirome at a dose of 25, 50, or 100 microg daily to statin treatment for 12 weeks reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively, (mean reduction from baseline, 7%, 22%, 28%, and 32%). Similar reductions were seen in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Eprotirome therapy was not associated with adverse effects on the heart or bone. No change in levels of serum thyrotropin or triiodothyronine was detected, although the thyroxine level decreased in patients receiving eprotirome. CONCLUSIONS: In this 12-week trial, the thyroid hormone analogue eprotirome was associated with decreases in levels of atherogenic lipoproteins in patients receiving treatment with statins. (ClinicalTrials.gov number, NCT00593047.)

Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex.

UNLABELLED: Secretion of cholesterol into bile is important for the elimination of cholesterol from the body. Thyroid hormone (TH) increases biliary cholesterol secretion and hepatic gene expression of adenosine triphosphate (ATP)-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8), two half-transporters that act as a heterodimeric complex promoting sterol secretion. In addition, nuclear liver x receptor-alpha (LXRa), also regulated by TH, induces gene expression of ABCG5/G8. We here investigated if the TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is involved. Mice homozygous for disruption of Abcg5 (Abcg5(-/-) ) or Lxra (Lxra(-/-) ) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was collected by gallbladder cannulation, and liver samples were analyzed for gene expression levels. Basal biliary cholesterol secretion in Abcg5(-/-) mice was 72% lower than in Abcg5(+/+) mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg5(+/+) mice, whereas this response was severely blunted in Abcg5(-/-) mice. In contrast, biliary cholesterol secretion in T3-treated Lxra(+/+) and Lxra(-/-) mice was increased 3.5- and 2.6-fold, respectively, and did not differ significantly. CONCLUSIONS: TH-induced secretion of cholesterol into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critical for this effect.

Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women.

OBJECTIVE: Cholesterol and lipoprotein metabolism display pronounced gender differences. Premenopausal women have lower LDL and higher HDL cholesterol, whereas men display higher synthetic rates of bile acids and cholesterol. The effects of the administration of exogenous hormones to humans and animals indicate that these gender differences can often be explained by estrogens. We evaluated how increased levels of endogenous estrogens modulate cholesterol and lipoprotein metabolism in women. METHODS AND RESULTS: We studied healthy women during initiation of in vitro fertilization using blood samples obtained when endogenous estrogens were low and high. Cholesterol in VLDL and LDL, but not in HDL, was reduced 20% when estrogens were high. Apolipoprotein B levels decreased 13%. Apolipoprotein A-I and triglyceride levels increased 8% and 37%, respectively, whereas lipoprotein(a) levels were unchanged. Circulating PCSK9, a suppressor of LDL receptors, was reduced 14% when estrogens were high. Serum markers of bile acid and cholesterol synthesis were unaltered. Growth hormone levels increased 3-fold when estrogens were high, whereas insulin-like growth factor-1 and fibroblast growth factor-21 concentrations were unaltered. CONCLUSION: In women, Apolipoprotein B-containing particles and circulating PCSK9 are reduced when endogenous estrogens are high, indicating that endogenous estrogens induce hepatic LDL receptors partly through a posttranscriptional mechanism. However, estrogens do not stimulate bile acid or cholesterol synthesis.

Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.

Dietary fat is an important source of nutrition. Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption. The Sar1 family of proteins initiates the intracellular transport of proteins in COPII (coat protein)-coated vesicles. Our data suggest that chylomicrons, which vastly exceed the size of typical COPII vesicles, are selectively recruited by the COPII machinery for transport through the secretory pathways of the cell.