Thirty-two patients (80%) were male. Mean value of serum HBV DNA was 5.1 logUI/ml (range 1.8-8.8 logUI/ml) and mean value of serum ALT was 116 IU/L (range 24-437 IU/L). Twelve patients (30%) were HBeAg-positive. After 48 weeks of follow-up, 7/40 patients (17.5%) achieved a SVR. Among them, 3/7 SVR patients (43%) had a loss of HBsAg, 5/7 (71%) have a HBsAg level below 100 IU/mL and 7/7 (100%) have a HBsAg below 1000 UI/mL. Comparison of variability VX-770 in vivo along the S protein by clonal analysis showed a higher percentage MHR variants in N-SVR compared to SVR patients (p=0.048). Furthermore, a higher frequency of mutated clones was observed in the “a determinant” region of N-SVR

vs SVR (p=0.049). This is known to be the main anti-HBs targets. The most frequent changes observed in N-SVR patients were located at position S126 and S133, which are known as immune escape variants. Conclusion: In patients receiving PEG-IFN plus TDF combination therapy, a SVR was observed in 17.5% of patients. N-SVR patients showed more variability along the S protein. The Accumulation of residue substitutions in and around the “a” determinant at baseline should be a sensitive predictor of response to combination of PegIFN and TDF therapy in CHB patients. Disclosures: Olivier Lada – Grant/Research

Wnt inhibitor Support: Gilead Nathalie Boyer – Board Membership: MSD, JANSSEN; Speaking and Teaching: BMS Tarik Asselah – Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen Patrick Marcellin – Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott The following people have nothing to disclose: Qian Zhang, Cédric Laouénan, Michelle Martinot-Peignoux, Martine Lapalus, Emilie Estrabaud Background & Aim: Nucleos(t)ide analogues currently approved by the U.S. FDA for

treatment of chronic HBV infection (CHB) include lamivudine selleck compound (3TC), adefovir (ADV), entecavir (ETV), telbivudine (LdT), and tenofovir (TDF). Current U.S. and European treatment guidelines for CHB recommend ETV or TDF as first-line therapy due to their increased potency and higher genetic barrier to DR than first-generation nucleos(t)ide analogues. We assessed frequency and distribution of HBV DR mutations in a large cohort of clinical specimens of U.S. origin submitted to a national reference testing laboratory (Mayo Medical Laboratories) from April 2007 to November 2012 for routine HBV GT and DR testing (performed at Quest Diagnostics, San Juan Capistrano, CA). Methods: Analyses were limited to HBV GT and DR distribution relative to gender, and geographic origins of specimens. Geographic locations of submitting laboratories were grouped according to the U.S.

The diagnosis of AIP can be a clinical challenge, because the price of misdiagnosis is heavy. Although AIP can mimic any know pancreatic disease, in practice, the chief differential diagnosis is pancreatic cancer. Thus, pancreatic Panobinostat manufacturer cancer diagnosed as AIP or vice versa can conceivably delay therapy for potentially-curable cancer or lead to unnecessary surgery. Thus, it is important to consider a few salient facts when diagnosing AIP. First, pancreatic

cancer is far more common, and second, the gold standard to diagnose AIP is histology.6,16,32 The presence of more than 10 IgG4-positive cells/high power field, along with other feature of AIP, that is LPSP or the presence of GEL, is diagnostic of AIP (see Histology). As obtaining pancreatic tissue for histology often involves invasive procedures (EUS-guided biopsy or pancreatic resection), the need for less invasive surrogates was realized. This led to the evolution of diagnostic criteria for AIP that try to limit pancreatic tissue sampling to only the most challenging cases. In addition, the exquisite sensitivity of AIP to steroid therapy is such

that in select situations, this response to therapy can itself be diagnostic. That said, the use of an empirical trial of corticosteroid therapy to diagnose AIP should be reserved for select situations with careful monitoring, and is strongly discouraged in the presence of features suggestive of pancreatic cancer. Selleck MAPK Inhibitor Library In 2002, the Japan Pancreas Society devised the first diagnostic criteria for AIP, and these were modified in 2006.33,34 The early emphasis was not to miss cases of resectable pancreatic cancer rather than to positively diagnose AIP. Since that time, a plethora of diagnostic criteria have been proposed. They

include the Italian criteria (2003 and 2009), the Mayo clinic HISORt criteria (Histology, Imaging, Serology, Other Organ Involvement and Response to Therapy 2006), the Korean criteria (2007), Asian Consensus criteria (2008), and the International Consensus criteria (2011).6,16,35Table 1 illustrates the HISORt criteria. Despite the numerous sets of diagnostic criteria for AIP, until recently, there have been no established algorithms to help differentiate AIP from pancreatic cancer. We recently published such an algorithm in an attempt selleck products to allow clinicians to select the various diagnostic tools available to differentiate AIP from pancreatic cancer (Table S2).36,37 Once the diagnosis of AIP has been established, corticosteroids are the mainstay of therapy. Recent studies have shown that corticosteroid therapy favorably alters the natural history of AIP; it hastens recovery, decreases complications, and improves symptoms.38,39 There are numerous dosing strategies, and to date, there have been no head-to-head comparisons between these. In our practice, we start with 40 mg/day prednisone orally for 1 month.

It had also become

apparent that very few persons with severe haemophilia who had received >50 EDs with plasma-derived FVIII, developed de novo inhibitors while on rFVIII. These findings led to the 1999 recommendation by the Scientific Subcommittee on RAD001 manufacturer Factor VIII and Factor IX of the ISTH’s Scientific and Standardization Committee that only previously (and heavily) treated haemophilia patients would be used for determining the immunogenicity of any new FVIII product [28]. Although the benefits of rFVIII products appeared to be enormous (increased viral safety, greater peace of mind), there was still some concern over the fact that the original rFVIII products, Kogenate and Recombinate, contained pasteurized human serum albumin (HSA) as a stabilizer. Pasteurized HSA had an excellent safety records, and there was no

indication that it caused any problems in recipients. Nevertheless, HSA was later replaced with sucrose as a stabilizer (e.g.: Kogenate FS, which is formulated with sucrose) [29–32]. As newer, so-called ‘second generation’ rFVIII products were developed, some clinicians worried that these might be more immunogenic. Pharmacia’s (Stockholm, Sweden) B-domainless rFVIII (rFVIII SQ) [33,34] entered prelicensure clinical trials in selleckchem 1993 in Europe, and in the U.S. in 1995. No albumin is needed to stabilize B-domainless rFVIII; however,

it was used in the manufacture of the product. B-domainless (BDD) rFVIII (ReFacto, now referred to as Xyntha, Wyeth Pharmaceuticals, Collegeville, PA), has not been associated with an increased incidence or prevalence of FVIII inhibitors as compared with plasma-derived or full-length rFVIII products in PTPs or PUPs [35–39]. From the introduction of the first rFVIII concentrates in the late 1980s, selleck screening library through each new variation, there have been carefully designed, long-term, prospective clinical trials in both PTPs and PUPs to look at safety and efficacy. These have included frequent inhibitor assays, as well as other laboratory and clinical observations. Each of these rFVIII preparations have proven to be safe and effective. None have resulted in an increased incidence or prevalence of inhibitors [40]. On the other hand, a large body of useful information has been gained from these (and other) studies which have improved our understanding as to which patients are at greater risk of developing an inhibitor, what are the important genetic and environmental risk factors; long-term viral safety of FVIII products, etc.

No differences were observed between MLCs and MSCs in either the magnitude or kinetics of the Ca2+ response to any of the nucleotides. When cultured

as described, both MSCs and MLCs developed an increase in transmembrane resistance by day 3 signifying the development of confluent monolayers with tight junctions (Fig. 4A). When mounted in an Ussing chamber, confluent MLCs BGJ398 concentration and MSCs monolayers exhibited a basal Isc, reflecting transepithelial secretion, which increased dramatically in response to the addition of ATP (100 μM) to the apical chamber (Fig. 4B,C). The nucleotide-stimulated Isc was significantly inhibited by the nonspecific Cl− channel blocker, 5-nitro-2-(-3-phenylpropylamino)-benzoic acid (NPPB), or by the Ca2+-activated Cl− channel blocker niflumic acid (Fig. 4C,F). Additionally, preincubation with the IP3 receptor blocker, 2-APB, significantly inhibited the ATP-stimulated increase in Iscin both MLC and MSC (Fig. 4C). In separate experiments, the effect of apical versus basolateral P2 receptor stimulation on the Isc was determined. For both MSCs and MLCs, an increase

in the Isc was observed when nucleotides were added to either chamber, consistent with functional expression of P2 receptors on both apical and basolateral membranes. The magnitude of the change in Isc was similar when nucleotides were added to either apical or basolateral compartments for all nucleotides tested except for UTP which caused a significantly greater increase in Isc when added apically versus basolateral Belnacasan order addition. Thus, both MSCs and

MLCs express functional P2 receptors on both apical and basolateral membranes. Nucleotide binding this website to P2 receptors causes an increase in [Ca2+]i, predominantly through an IP3 receptor-dependent mechanism, which stimulates Ca2+-activated Cl− channels, and results in transepithelial secretion. To our knowledge, these represent the first integrated Isc measurements of transepithelial secretion in mouse cholangiocytes. Furthermore, in MSC, which do not express CFTR, Ca2+-activated Cl− efflux in response to extracellular nucleotides represents the first secretory pathway clearly identified in these cells derived from the small intrahepatic ducts. In human biliary cells and normal rat cholangiocyte monolayers, mechanical stimulation,22 shear stress,13 and cell swelling secondary to hypotonic exposure,22 have all been identified as significant stimuli for ATP release. Studies were performed to determine if these mechanical stimuli result in a similar increase in the magnitude of ATP release in mouse cholangiocytes. First, in response to hypotonic exposure (33% dilution) to stimulate cell swelling, a rapid and large increase in ATP release was observed in both MLCs and MSCs (Fig. 5A). The magnitude of the response, which peaked within 30 seconds, was significantly greater in MSCs versus MLCs (Fig. 5A,C).

No differences were observed between MLCs and MSCs in either the magnitude or kinetics of the Ca2+ response to any of the nucleotides. When cultured

as described, both MSCs and MLCs developed an increase in transmembrane resistance by day 3 signifying the development of confluent monolayers with tight junctions (Fig. 4A). When mounted in an Ussing chamber, confluent MLCs Selleck RXDX-106 and MSCs monolayers exhibited a basal Isc, reflecting transepithelial secretion, which increased dramatically in response to the addition of ATP (100 μM) to the apical chamber (Fig. 4B,C). The nucleotide-stimulated Isc was significantly inhibited by the nonspecific Cl− channel blocker, 5-nitro-2-(-3-phenylpropylamino)-benzoic acid (NPPB), or by the Ca2+-activated Cl− channel blocker niflumic acid (Fig. 4C,F). Additionally, preincubation with the IP3 receptor blocker, 2-APB, significantly inhibited the ATP-stimulated increase in Iscin both MLC and MSC (Fig. 4C). In separate experiments, the effect of apical versus basolateral P2 receptor stimulation on the Isc was determined. For both MSCs and MLCs, an increase

in the Isc was observed when nucleotides were added to either chamber, consistent with functional expression of P2 receptors on both apical and basolateral membranes. The magnitude of the change in Isc was similar when nucleotides were added to either apical or basolateral compartments for all nucleotides tested except for UTP which caused a significantly greater increase in Isc when added apically versus basolateral selleck screening library addition. Thus, both MSCs and

MLCs express functional P2 receptors on both apical and basolateral membranes. Nucleotide binding selleck to P2 receptors causes an increase in [Ca2+]i, predominantly through an IP3 receptor-dependent mechanism, which stimulates Ca2+-activated Cl− channels, and results in transepithelial secretion. To our knowledge, these represent the first integrated Isc measurements of transepithelial secretion in mouse cholangiocytes. Furthermore, in MSC, which do not express CFTR, Ca2+-activated Cl− efflux in response to extracellular nucleotides represents the first secretory pathway clearly identified in these cells derived from the small intrahepatic ducts. In human biliary cells and normal rat cholangiocyte monolayers, mechanical stimulation,22 shear stress,13 and cell swelling secondary to hypotonic exposure,22 have all been identified as significant stimuli for ATP release. Studies were performed to determine if these mechanical stimuli result in a similar increase in the magnitude of ATP release in mouse cholangiocytes. First, in response to hypotonic exposure (33% dilution) to stimulate cell swelling, a rapid and large increase in ATP release was observed in both MLCs and MSCs (Fig. 5A). The magnitude of the response, which peaked within 30 seconds, was significantly greater in MSCs versus MLCs (Fig. 5A,C).

Estrogen as an ingredient of learn more OC might be a responsible factor for these observations. We conducted the present study to test whether OC are able to alter the severity of headache

attacks as well as the detection or pain thresholds over the course of the menstrual cycle in patients with migraine. Methods.— Thirteen healthy and regularly menstruating women and 26 migraineurs (13 using OC and 13 not using OC) were studied on the days 1, 4, 14, and 22 of their menstrual cycle. In all participants, saliva was collected first for determination of estrogen on each study day. Then, detection thresholds (warmth, cold, electrical current) and pain thresholds (cold, heat, pressure, electrical current) were assessed. Migraineurs were asked for headache attacks occurring in a period of 24 hours before testing and to estimate pain intensity on a verbal rating scale. selleck kinase inhibitor Results.— On day 4 of the menstrual cycle, migraineurs using OC suffered significantly more from severe migraine attacks than migraineurs not taking OC. With respect to detection and pain thresholds, no effects of OC could be observed as concerning the differences between migraineurs with or without OC medication. On day 22, the severity

of migraine headache was significantly related with the pain thresholds for pressure and electrical current, suggesting paradoxically more severe headache attacks in patients presenting with higher pain thresholds. Healthy volunteers disclosed higher salivary estrogen levels than migraineurs and migraineurs not using OC higher concentrations than migraineurs using OC throughout the menstrual cycle. Conclusions.— In this study, the use of OC intensified migraine (however only at the end of menstruation) however had no influence on detection and pain thresholds in migraineurs. Possible reasons for this dissociation will be discussed. “
“(Headache 2010;50:1089-1099) Background.— In 2006, a US Food and Drug Administration (FDA) alert warned about the potential

life-threatening risk of serotonin syndrome when triptans are used in combination with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). This American Headache Society Position Paper further reviews the available evidence of the potential risk of combining triptans with other serotonergic agents. Methods.— Using the Sternbach Criteria or the Hunter Serotonin selleck inhibitor Toxicity Criteria, the 29 cases used as the basis for the FDA alert were assessed in addition to a more recently published clinical review of 11 case reports of serotonin syndrome resulting from monotherapy, and one report of combination serotonergic agents. Evidence was evaluated according to the American Academy of Neurology Clinical Practice Guideline Process Manual. Results.— Collectively, 40 case reports are available in the literature for subjects receiving either combination or monotherapy of serotonin agonists, all of which are limited to Class IV level of evidence.

2, 4, 5 Of the three members of the PPAR subfamily, PPARγ is critical for conserving energy as it contributes to adipogenesis,2, 4, 6-9 whereas both PPARα and PPARβ participate in energy expenditure.2,

5 PPARγ, which has two isoforms, PPARγ1, and an N-terminal 30–amino acid extended form PPARγ2 (henceforth referred to simply as PPARγ), is expressed at a relatively high level in adipose tissue, where it serves as a regulator of adipocyte differentiation and promotes energy storage in mature adipocytes.7, 8 Of particular interest is that overexpression of PPARγ in mouse liver leads to adipogenic hepatic steatosis (“hepatic adiposis”) and induces the expression of adipocyte-specific and

selleck screening library lipogenesis-related genes.6 In contrast, liver-specific disruption of PPARγ exerts an opposite effect in that it dramatically reduces fatty liver.9, 10 Thus, PPARγ plays an important role in liver lipid metabolism and contributes to hepatic steatosis. In the nucleus, PPARs heterodimerize with retinoid X receptor α and bind to peroxisome proliferator response elements in the promoter region of target genes.4, 11, 12 Transcriptional activity of nuclear receptors and other transcription factors requires certain coactivators and coactivator-associated proteins that include PBP/TRAP220 (Refs. 13-15) and /DRIP205/ARC/MED1

click here (henceforth referred to as MED1; reviewed in Refs. 15-17), SRC (steroid receptor coactivator)/p160 BVD-523 ic50 family of proteins)18 and others (reviewed in Refs. 17 and 19). Identification of an increasing array of coactivators in recent years raises new challenges about their specific functional role in PPAR action and lipid metabolism in liver.17, 18 Evidence indicates that coactivator MED1, the best-studied subunit of the 31 member mammalian Mediator complex,12-16 is required for PPARα-mediated transcriptional activity in vivo,20 for PPARα ligand-induced liver tumor development,21 and PPARγ-stimulated adipogenic differentiation in vitro,22 but the in vivo role of this and other coactivators in liver with regard to PPARγ function remains largely unknown. To delineate the in vivo function of coactivator molecules in PPARγ-stimulated adipogenic hepatic steatosis, we used genetically altered mouse lineages in this study and we demonstrate that deletion of MED1 in mouse liver (MED1ΔLiv) impairs high-fat diet–induced and PPARγ-stimulated hepatic steatosis, whereas deficiency of coactivators such as SRC-1, PRIC285, PRIP, and PIMT had no effect. Thus, liver MED1 contributes to hepatic steatosis as it is required for PPARγ function.

The relationship between methionine deficiency and fatty acid/eicosanoid metabolism is under investigation. The findings in the present study suggest that serum levels of LPC and bile acids are altered with disease severity and progression also in alcoholic liver disease. Additionally, it may be of great interest to investigate the differences in serum metabolites between alcoholic steatohepatitis and NASH. Future studies would answer these questions. Lastly, the metabolomic analysis in the current study is advantageous in detecting global metabolite

changes in an unbiased manner. Of the numerous endogenous serum metabolites, LPC and bile acids were selected as selleck screening library metabolites that were significantly altered in mice with NASH. Indeed, the increases in taurocholate and the decreases in some kinds of LPC have been reported in serum of NASH patients.37, 38 Thus, the mechanism proposed in this study might apply to humans. In addition, these results provide the possibility that the metabolomic approach could detect serum biomarkers for discrimination between steatosis and steatohepatitis. this website Future large-scale metabolomic studies using serum of NAFLD/NASH patients might lead to the identification of biomarkers of clinical diagnostic value for NASH. We thank Linda Byrd and John Buckley for animal management. Additional Supporting Information may be found in the

online version of this article. “
“Autophagy is a stress response that is upregulated in response to signals such as starvation, growth selleck chemical factor

deprivation, endoplasmic reticulum stress, and pathogen infection. Defects in this pathway are the underlying cause of a number of diseases, including metabolic aberrations, infectious diseases, and cancer, which are closely related to hepatic disorders. To date, more than 30 human ATG (autophagy) genes have been reported to regulate autophagosome formation. In this review, we summarize the current understanding of how ATG proteins behave during autophagosome formation in both non-selective and selective autophagy. “
“Background and aims: Increasing evidence suggests that genetic factors play a role in the development of liver fibrosis. An association between several single nucleotide polymorphisms (SNPs) and the extent of hepatic fibrosis in patients with viral hepatitis or non-alcoholic fatty liver disease (NAFLD) has been described. Aim of this study was to investigate the association between these SNPs and liver stiffness measurements (LSM) in a population-based cohort of healthy participants. Methods: This study was based on the Rotterdam study, a large population-based cohort study of subjects aged 55 years or older. Liver fibrosis was noninvasively assessed with transient elastography. Abdominal ultrasound was performed to diagnose NAFLD.

19 Loss of PHB2 in MEFs was accompanied by loss of PHB1, confirming their interdependence in the mammalian system. Loss of PHB2 resulted in aberrant mitochondrial cristae morphogenesis

and increased apoptosis, which is similar to Phb1 KO. However, loss of PHB2 in MEFs led to impaired cellular proliferation.19 Given that these two proteins function as a complex at least in the mitochondria, it is intriguing that they should have such different effects on growth. Our findings are consistent with an earlier report; during liver regeneration in rats, where the expression of PHB1 is abundant in quiescent hepatocytes and nearly absent during the 3-hour to 12-hour period following two-thirds partial hepatectomy, and returning to normal levels at 24 hours.28 These changes correlated with entry of hepatocytes into the cell cycle and support the notion that a fall in PHB1 facilitates Protease Inhibitor Library cell line cell-cycle entry and proliferation. Based on the findings thus far, reduced PHB1 expression that occurs in the Mat1a KO livers can contribute to liver injury, increased oxidative stress, impaired mitochondrial

function, expansion of liver progenitor cells, and development of HCC in the Mat1a KO mouse model.10–12, 29 However, whether it also contributes to the susceptibility to develop fatty liver in the Mat1a KO mice12 is not clear. Although there is no evidence for increased fat accumulation in Phb1 KO livers click here up to 14 weeks of age, there is increased

plasma cholesterol selleck compound level, which may signal impairment in cholesterol uptake by the liver. This possibility will require further investigation. In summary, liver-specific deletion of Phb1 results in marked liver injury at an early age that is characterized by necrosis, apoptosis, swollen mitochondria, oxidative stress, fibrosis, and increased expression of progenitor cell and preneoplastic markers. Multifocal HCC occurs by 8 months. Marked reduction of PHB1 alters the expression of genes involved in multiple cellular pathways, from growth, inflammation, and xenobiotic metabolism. Our study demonstrates for the first time a vital role for PHB1 in normal liver physiology and supports PHB1 as a tumor suppressor in liver. CIBERehd is funded by the Instituto de Salud Carlos III. Isolated mouse hepatocytes were prepared by the Cell Culture Core, whereas liver tissue sectioning and hematoxylin and eosin (H&E) staining were performed by the Cell and Tissue Imaging Core of the USC Research Center for Liver Diseases (P30DK48522). Immunohistochemistry for 4-HNE, reticulin, OV-6, GSTP, and AFP were done by the Morphology Core of the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis (P50AA11999).

38 In other studies, statins neither influenced biliary cholesterol secretion nor reduced cholesterol saturation indices in general.39 The data from our patients, which are given as means, indicate that subgroups of patients are at higher (genetic) risk of stone formation. In these cases, increased cholesterol synthesis could be a critical additional factor driving stone formation, and they could benefit from drugs lowering cholesterol

CT99021 mouse synthesis, which has indeed been observed on an individual basis.40 With respect to ezetimibe, studies in mouse models and a single study in humans41, 42 have shown that it can reduce biliary cholesterol secretion and cholesterol concentrations in gallbladder bile. In this respect, future prospective studies using surrogate markers of cholesterol synthesis and transport in large cohorts of patients under cholesterol-lowering therapy are warranted. Previously, it has been postulated that in selected patients ratios of serum campesterol and sitosterol to cholesterol reflect the biliary cholesterol secretion rates.43 Because in our study we used the surrogate markers for cholesterol transport

and synthesis, which indicated a link between cholesterol homeostasis and GSD, we further strengthened our findings by analysis of biliary lipid compositions, demonstrating that gallstone patients display increased biliary levels of both phytosterols and cholesterol. These results are in line with data published by Miettinen et al.44 Their

analysis of 150 individuals with cholesterol stones showed preferentially increased Selleckchem GW 572016 levels of plant sterols in bile from cholesterol gallstone patients.44 The latest analysis of a cohort of pediatric patients with gallstones indicated that increased cholesterol synthesis selleck compound and decreased cholesterol absorption are likely to underlie the formation of gallbladder stones in younger individuals.45 Interestingly, the same profile is characteristic for another liver phenotype, fatty liver disease.46 As fatty liver is one of the risk factors for gallstone formation,47 distorted cholesterol homeostasis may represent a metabolic link between both entities. Moreover, we observed pronounced differences across the ethnic groups (Fig. 2). These results, together with lower cholesterol levels in Chilean individuals as compared with Germans, point to a more pronounced prolithogenic phenotype in Chileans and at least partially explain the previously reported differences of gallstone prevalence rates among the ethnicities included in the current study.21-23 In summary, serum sterol levels represent surrogate markers indicating that gallstone-susceptible patients display enhanced secretion of cholesterol and non-cholesterol sterols into bile, which is coupled with an increased synthesis of new cholesterol. Furthermore, increased cholesterol synthesis might be secondary to decreased intestinal cholesterol absorption resulting from gain-of-function of the ABCG5/8 transporter system.