Statins have been reported to reduce the risk of gallstone disease. However, the impacts of different durations of statin use on gallstone disease have not been clarified. The aim of this study is toperform a systematic review with meta-analysis to update and to elucidate the association between statin use and the risk of gallstone disease and cholecystectomy.

Medline, Embase and Cochrane Library were searched from the inception until August 2022 for relevant articles investigating the difference in the risk of gallstone disease between statin users and non-users (PROSPERO, ID: CRD42020182445). Meta-analyses were conducted using odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to compare the risk of gallstone disease and cholecystectomy between statin user and nonusers.

Eight studies enrolling 590,086 patients were included. Overall, the use of statins was associated with a marginally significant lower risk of gallstone disease than nonusers (OR, 0.91; 95% CI [0.82-1.00]). Further subgroup analysis showed that short-term users, medium-term users, and long-term users were associated with a significantly higher risk (OR, 1.18; 95% CI [1.11-1.25]), comparable risk (OR, 0.93; 95% CI [0.83-1.04]), and significantly lower risk of gallstone diseases (OR, 0.78; 95% CI [0.68-0.90]) respectively, compared to nonusers.

Patients with medium-term or long-term use of statins without discontinuation are at a lower risk of gallstone disease or cholecystectomy.

Statins are suggested to preserve gallbladder function by suppressing pro-inflammatory cytokines and preventing cholesterol accumulation in gallbladder epithelial cells. They also affect cross-talk among the nuclear hormone receptors that regulate cholesterol-bile acid metabolism in the nuclei of hepatocytes. However, there is controversy over whether or how statins change the expression of peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, liver X receptor alpha (LXRalpha), farnesoid X receptor (FXR), ABCG5, ABCG8, and 7alpha-hydroxylase (CYP7A1) which are directly involved in the cholesterol saturation index in bile.

Human Hep3B cells were cultured on dishes. MTT assays were performed to determine the appropriate concentrations of reagents to be used. The protein expression of PPARalpha and PPARgamma was measured by Western blotting analysis, and the mRNA expression of LXRalpha, FXR, ABCG5, ABCG8 and CYP7A1 was estimated by RT-PCR.

In cultured Hep3B cells, pravastatin activated PPARalpha and PPARgamma protein expression, induced stronger expression of PPARgamma than that of PPARalpha, increased LXRalpha mRNA expression, activated ABCG5 and ABCG8 mRNA expression mediated by FXR as well as LXRalpha, enhanced FXR mRNA expression, and increased CYP7A1 mRNA expression mediated by the PPARgamma and LXRalpha pathways, together or independently.

Our data suggested that pravastatin prevents cholesterol gallstone diseases via the increase of FXR, LXRalpha and CYP7A1 in human hepatocytes.

No indices are currently available to facilitate clinicians to identify patients who need either statin monotherapy or statin-ezetimibe combined treatment. We aimed to investigate whether cholesterol synthesis and absorption markers can predict the cholesterol-lowering response to statin. Total 306 statin-naïve patients with high risk of coronary heart disease (CHD) were treated with atorvastatin 20 mg/day for 1 month. Cholesterol synthesis and absorption markers and LDL cholesterol (LDL-C) levels were measured before and after treatment. Atorvastatin decreased LDL-C by 36.8% (range: decrease of 74.5% to increase of 31.9%). Baseline cholesterol synthesis marker lathosterol and cholesterol absorption marker campesterol codetermined the effect of atorvastatin treatment. The effect of cholesterol lowering by atorvastatin was significantly associated with baseline lathosterol levels but modified bidirectionally by baseline campesterol levels. In patients with the highest baseline campesterol levels, atorvastatin treatment decreased cholesterol absorption by 46.1%, which enhanced the effect of LDL-C lowering. Atorvastatin treatment increased cholesterol absorption by 52.3% in those with the lowest baseline campesterol levels, which attenuated the effect of LDL-C reduction. Especially those with the highest lathosterol but the lowest campesterol levels at baseline had significantly less LDL-C reduction than those with the same baseline lathosterol levels but the highest campesterol levels (27.3% versus 42.4%, P = 0.002). These results suggest that combined patterns of cholesterol synthesis/absorption markers, rather than each single marker, are potential predictors of the LDL-C-lowering effects of atorvastatin in high-risk CHD patients.

Cholesterol cholelithiasis is a multifactorial disease influenced by a complex interaction of genetic and environmental factors and represents a failure of biliary cholesterol homoeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed.

The primary pathophysiologic event is persistent hepatic hypersecretion of biliary cholesterol, which has both hepatic and small intestinal components. The majority of the environmental factors are probably related to Western-type dietary habits, including excess cholesterol consumption.

Laparoscopic cholecystectomy, one of the most commonly performed surgical procedures in the United States, is nowadays a major treatment for gallstones. However, it is invasive and can cause surgical complications, and not all patients with symptomatic gallstones are candidates for surgery. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been employed as first-line pharmacological therapy in a subgroup of symptomatic patients with small, radiolucent cholesterol gallstones. Long-term administration of UDCA can promote the dissolution of cholesterol gallstones. However, the optimal use of UDCA is not always achieved in clinical practice because of failure to titrate the dose adequately.

Therefore, the development of novel, effective and noninvasive therapies is crucial for reducing the costs of health care associated with gallstones. In this review, we summarize recent progress in investigating the inhibitory effects of ezetimibe and statins on intestinal absorption and hepatic biosynthesis of cholesterol, respectively, for the treatment of gallstones, as well as in elucidating their molecular mechanisms by which combination therapy could prevent this very common liver disease worldwide.

Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.

Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase inhibitors) reduce blood lipoproteins and reduce the risk of cardiovascular events. However, they may reduce fat metabolism. This study tested the hypothesis that total body fat oxidation is reduced by statins in older subjects and the reduction is not due to substrate availability.

A total of 14 elderly patients (71 ± 6 years) on statin therapy were compared with 14 matched elderly controls (75 ± 7 years). Subjects were tested for respiratory exchange ratio (RER) during both maximal and submaximal sustained (70% Vo(2max)) exercise to voluntary exhaustion. Blood samples were drawn for lipoprotein analysis and substrate availability.

RER was significantly higher in subjects taking statins during both the max and submax tests, indicating reduced fat oxidation. Blood lipoprotein levels after a fast were not different between the statin and control groups. Levels of glucose, lactate, or triglyceride were not different between groups; however, free fatty acid levels were elevated by exercise in the statin group. Fat oxidation was significantly reduced in older subjects taking statin drugs that were not associated with diet, exercise, and fitness, which were matched between groups, nor availability of fat from the blood, which was higher in the statin group.

Although statin therapy normalizes blood lipoproteins, it reduced fat metabolism in older individuals, which cannot be a result of lower availability from blood.

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors, increasing age, female gender, and metabolic factors. Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones, new perspectives regarding medical therapy of cholelithiasis are currently under discussion, also taking into account the pathogenesis of gallstones, the natural history of the disease and the analysis of the overall costs of therapy. A careful selection of patients may lead to successful non-surgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones. The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations, suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, might be proposed as additional approaches for treating cholesterol gallstones. In this review we discuss old, recent and future perspectives on medical treatment of cholesterol cholelithiasis.

The aim of this study was to investigate whether the use of statins was associated with a decreased risk of gallstone disease.

We conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of gallstone disease or cholecystectomy for the period between 2005 and 2009. The controls were matched to cases by age, sex and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression.

We examined 1014 gallstone disease cases and 1014 controls. The unadjusted ORs for any statin prescription was 1.06 (95% CI 0.86 to 1.29), and the adjusted OR was 1.14 (95% CI 0.90 to 1.43). Compared with no use of statins, the adjusted ORs were 1.05 (95% CI 0.72 to 1.54) for the group having been prescribed statins with cumulative defined daily doses (DDDs) below 41.53, 1.12 (95% CI 0.84 to 1.50) for the group with cumulative dose between 41.54 and 334.81 DDD, and 1.30 (95% CI 0.86 to 1.95) for the group with cumulative statin use of 334.81 DDDs or more.

This study does not provide support for a beneficial association between usage of statin and gallstone disease.

Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decreases in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. Cholesterol gallstones are a common problem, resulting in hospital admission and surgery, throughout western healthcare systems.

This review describes the mechanisms, and addresses the potential, for statins to be used as a treatment for gallstones. Medline was searched for the risk factors and treatment of cholesterol gallstones.

Obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), insulin resistance and high-fat diets (unsaturated fats) rich in cholesterol are all associated risk factors for cholesterol gallstones. In view of the high prevalence of cholesterol gallstones, there is an urgent need to understand whether pharmacological therapies can be harnessed for the treatment of cholesterol gallstones. Gallstones are shown to be associated with an increased risk, not only of mortality, but also of CVD. Statins, widely used in prevention of CVD and hypercholesteremia, have been shown to dissolve cholesterol gallstones in animal models and human studies, highlighting the potential for a pharmacological therapy for gallstones. More studies are required to understand the role of statins in the treatment of gallstones and for comparison with current treatment strategies.

Most gallstones originate from cholesterol-supersaturated bile. Statins inhibit hepatic cholesterol biosynthesis and therefore may reduce the risk of gallstone disease. Population-based evidence, however, is sparse. Thus, the authors conducted a population-based case-control study using medical databases from northern Denmark (1.7 million inhabitants) to identify 32,494 cases of gallstones occurring between 1996 and 2008 and to identify age-, sex-, and county-matched population controls for each case. Cases and their matched controls who were exposed to lipid-lowering drugs were categorized as current users if their last prescription was redeemed ≤90 days before the case's diagnosis date; otherwise, they were categorized as former users. Conditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals for gallstone disease in patients treated with lipid-lowering drugs. In current users, the adjusted odds ratios associating statin use with the occurrence of gallstone disease were 1.17 (95% confidence interval (CI): 1.06, 1.30) for those who had 1-4 prescriptions, 0.89 (95% CI: 0.80, 0.97) for those who had 5-19 prescriptions, and 0.76 (95% CI: 0.69, 0.84) for those who had ≥20 total prescriptions. In former users, the corresponding adjusted odds ratios were 1.24 (95% CI: 1.11, 1.39), 0.97 (95% CI: 0.86, 1.10), and 0.79 (95% CI: 0.64, 0.97), respectively. The use of other lipid-lowering drugs showed no similar association.

Gallstone disease is a frequent condition throughout the world and, cholesterol stones are the most frequent form in Western countries. The standard treatment of symptomatic gallstone subjects is laparoscopic cholecystectomy. The selection of patients amenable for nonsurgical, medical therapy is of key importance; a careful analysis should consider the natural history of the disease and the overall costs of therapy. Only patients with mild symptoms and small, uncalcified cholesterol gallstones in a functioning gallbladder with a patent cystic duct are considered for oral litholysis by hydrophilic ursodeoxycholic acid, in the hope of achieving cholesterol desaturation of bile and progressive stone dissolution. Recent studies have raised the possibility that cholesterol-lowering agents that inhibit hepatic cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, may offer, alone or in combination, additional medical therapeutic tools for treating cholesterol gallstones. Recent perspectives on medical treatment of cholesterol gallstone disease are discussed in this article.

In gallbladder epithelial cells (GBEC), PPARalpha and PPARgamma ligands modulate inflammation by suppression of TNFalpha production and prevent excessive accumulation of cholesterol by ABCA1 activation. Recently, HMG-CoA reductase inhibitors (statins) were shown to activate PPARalpha and PPARgamma in various cells but no studies of their effects in GBEC have been conducted. The objective of this study was, therefore, to determine the effects of statins on PPAR and ABCA1 expression and the anti-inflammatory effect of statins in GBEC. Canine GBEC were cultured on Petri dishes. Expression of the proteins PPARalpha, PPARgamma, and ABCA1 was measured by western blotting analysis after treatment with simvastatin, pravastatin, NO-pravastatin, PPARalpha ligand, or PPARgamma ligand in the culture media. Expression of ABCA1 and LXRalpha mRNAs was estimated by RT-PCR. Expression of TNFalpha mRNA was measured by RT-PCR after 24 h pre-treatment with the statins, preceding 1 h of lipopolysaccharide (LPS) loading. Simvastatin, pravastatin, and NO-pravastatin increased expression of the proteins PPARalpha, PPARgamma, and ABCA1, and expression of the mRNA of ABCA1 and LXRalpha in GBEC. Pre-treatment with simvastatin, pravastatin, and NO-pravastatin suppressed the production of TNFalpha mRNA induced by LPS. In conclusion, statins probably contribute to the preservation of GBEC function by activation of PPARalpha and PPARgamma, which have anti-inflammatory effects by suppression of pro-inflammatory cytokines, and ABCA1 activation mediated by LXRalpha, which prevents the accumulation of cholesterol in GBEC.

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

Statins can reduce biliary cholesterol secretion independently of their ability to inhibit cholesterol synthesis. Statins also prevent the formation of gallstones in animal studies, although the effect of statins on human gallstone disease has been controversial.

We examined the relationship between the use of statins and the risk of cholecystectomy in a cohort of US women. As part of the prospective Nurses' Health Study, participants biennially reported their history of gallstone disease and whether they had undergone cholecystectomy. Women also reported lifetime use of statins retrospectively in 2000. We conducted a retrospective analysis of statin using data collected in 2000, to define use from 1994 forward, and a prospective analysis for general lipid-lowering drugs from 1994 to 2004.

In the statin analysis we ascertained 2479 cases of cholecystectomy during 305,197 person-years of follow-up evaluation. The multivariate relative risk for current statin users, compared with nonusers, was 0.82 (95% confidence interval, 0.70-0.96). In the analysis of general cholesterol-lowering drugs, we ascertained 3420 cases of cholecystectomy during 511,411 person-years of follow-up evaluation. Compared with nonusers, the multivariate relative risk for current users of general cholesterol-lowering drugs, mostly statins in this cohort, was 0.88 (95% confidence interval, 0.79-0.98).

Statin use appears to reduce the risk of cholecystectomy in women.

This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). Simvastatin did not significantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.

The absorption of cholesterol by the proximal small intestine represents a major pathway for the entry of cholesterol into the body pools. This cholesterol is derived primarily from the bile and the diet. In adult humans, typically several hundred milligrams of cholesterol reach the liver from the intestine daily, with the potential to impact the plasma low density lipoprotein-cholesterol (LDL-C) concentration. There are three main phases involved in cholesterol absorption. The first occurs intraluminally and culminates in micellar solubilization of unesterified cholesterol which facilitates its movement up to the brush border membrane (BBM) of the enterocyte. The second phase involves the transport of cholesterol across the BBM by Niemann-Pick C1 Like-1 (NPC1L1), while the third phase entails a series of steps within the enterocyte involving the esterification of cholesterol and its incorporation, along with other lipids and apolipoprotein B48 (apo B48), into nascent chylomicrons (CM). The discovery of the role of NPC1L1 in intestinal sterol transport occurred directly as a consequence of efforts to identify the molecular target of ezetimibe, a novel, potent, and specific inhibitor of sterol absorption that is now widely used in combination therapy with statins for the management of hypercholesterolemia in the general population. Some aspects of the role of NPC1L1 in cholesterol absorption nevertheless remain controversial and are the subject of ongoing research. For example, one report suggests that NPC1L1 is located not in the plasma membrane but intracellularly where it is thought to be involved in cytosolic trafficking of cholesterol, while another concludes that a protein other than NPC1L1 is responsible for the high affinity binding of cholesterol on intestinal BBM. However, other new studies which show that the in vivo responsiveness of different species to ezetimibe correlates with NPC1L1 binding affinity further support the widely held belief that NPC1L1 does facilitate sterol uptake by the enterocyte and is the target of ezetimibe. Added to this is the unequivocal finding that deletion of the gene for NPC1L1 in mice results in a near complete prevention of cholesterol absorption and an accelerated rate of fecal neutral sterol excretion. In summary, the development of ezetimibe and the identification of NPC1L1 as a key player in sterol absorption have taken research on the molecular control of this pathway to an exciting new level. From this it is hoped that we will now be able to determine more precisely what effect, if any, other classes of lipid lowering agents, particularly the statins, might exert on the amount of intestinal cholesterol reaching the liver.

Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.

To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.

A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10 mg, simvastatin (10-80 mg), and atorvastatin (10-80 mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipo protein [LDL-C] = 145-250 mg/dL; triglycerides < or = 350 mg/dL; N = 975) but without a recent (< or = 6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.

Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p < 0.001), whereas statins significantly lowered desmo sterol and lathosterol levels (p < 0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p < 0.001).

The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe-statin) doses and circulating non-cholesterol levels.

Cholesterol lowering drugs are associated with myopathic side effects in 7% of those on therapy, which is reversible in most, but not all patients. This study tested the hypothesis that total body fat oxidation (TBFO) is reduced by statins in patients with genetic deficiencies in FO, determined by white blood cells (FOwbc) and by molecular analysis of common deficiencies, and would cause intolerance in some patients. Six patients on statin therapy without myopathic side effects (tolerant) and 7 patients who had previously developed statin-induced myopathic symptoms (intolerant) (age = 58 +/- 8.25 yrs, ht. = 169 +/- 11 cm, and wt. = 75.4 +/- 14.2 kg) were tested for TBFO (Respiratory Exchange Ratio, RER) pre- and during exercise. FOwbc was not significantly different between tolerant and intolerant (0.261 +/- 0.078 vs. 0.296 +/- 0.042 nmol/h per 10(9) wbc), or normals (0.27 +/- 0.09 nmol/h per 10(9) wbc) and no common molecular abnormalities were found. Pre-exercise RER (0.73 +/- 0.05 vs. 0.84 +/- 0.05) was significantly lower in the intolerant group and the VO2 at RER = 1.0 (1.27 +/- 0.32 vs. 1.87 +/- 0.60 L/min) greater than the tolerant. Post-exercise lactates were not different between groups. Although dietary fat intake was not different, blood lipoprotein levels, particularly triglycerides were 35% lower in tolerant than previously intolerant. TBFO and blood lipoproteins were reduced in tolerant patients in spite of the absence of genetic limitations, but not in the intolerant group as hypothesized. Although not conclusive, these data suggest the need for a prospective study of the effects of statins on fat oxidation.

Cholesterol absorption and synthesis contribute to maintaining cholesterol homeostasis. Several physiological and therapeutic factors affect cholesterol homeostasis, including: genetics, circadian rhythm, body weight, plant sterols, ezetimibe, and statin therapy. The present objective is to determine the main vector, i.e. cholesterol absorption or synthesis, affected by each of these factors, and to examine whether an alteration in one vector is linked to a reciprocal change in the other. Current techniques used to assess cholesterol absorption and synthesis are also reviewed. Review of physiological factors affecting cholesterol metabolism suggest a reciprocal relationship between these two vectors. Carriers of the E2 isoform of apolipoprotein E and ATP binding cassette (ABC) G8 19H (exon 1 mutation) show a decrease in cholesterol absorption accompanied by a corresponding increase in synthesis. Circadian rhythm affects cholesterol synthesis, however, its effect on absorption has yet to be established. Obese subjects show an increase in cholesterol synthesis with a subsequent decrease in cholesterol absorption. Weight loss down regulates cholesterol synthesis, but has little or no effect on absorption. In the case of therapeutic factors, plant sterols and stanols inhibit cholesterol absorption, which results in a compensatory increase in synthesis. Ezetimibe also decreases intestinal absorption, while reciprocally increasing synthesis. Statin therapy down regulates synthesis, which is accompanied by a rise in absorption. These findings suggest that a change in one vector, fairly consistently, results in a compensatory and opposing change in the other. An understanding of this reciprocal relationship between cholesterol absorption and synthesis may allow for the development of more effective interventions for dyslipidemic disorders.

ACAT (also called sterol o-acyltransferase) catalyzes the esterification of cholesterol by reaction with long-chain acyl-CoA derivatives and plays a pivotal role in the regulation of cholesterol homeostasis. Although two human ACAT genes termed ACAT-1 and ACAT-2 have been reported, prior research on differential tissue expression is qualitative and incomplete. We have developed a quantitative multiplex assay for each ACAT isoform after RT treatment of total RNA using TaqMan real-time quantitative PCR normalized to beta-actin in the same reaction tube. This enabled us to calculate the relative abundance of transcripts in several human tissues as an ACAT-2/ACAT-1 ratio. In liver (n = 17), ACAT-1 transcripts were on average 9-fold (range, 1.7- to 167-fold) more abundant than ACAT-2, whereas in duodenal samples (n = 10), ACAT-2 transcripts were on average 3-fold (range, 0.39- to 12.2-fold) more abundant than ACAT-1. ACAT-2 was detected for the first time in peripheral blood mononuclear cells. Interesting differences in ACAT-2 mRNA expression were evident in subgroup analysis of samples from different sources. These results demonstrate quantitatively that ACAT-1 transcripts predominate in human liver and ACAT-2 transcripts predominate in human duodenum and support the notion that ACAT-2 has an important regulatory role in liver and intestine.

Ginseng is one of the most popular herbal remedies. Studies were performed in anaesthetized rats to examine the effect of ginseng on bile secretion. Male Sprague-Dawley rats were anaesthetized with intraperitoneal (i.p.) urethane (1.25 g kg(-1)) and equipped with biliary cannulas inserted into the bile duct through the sphincter of Oddi. Rats were treated with a single i.p. injection of ginseng at 25, 50 or 100 mg kg(-1) (1 ml(-1)) 30 min before bile collection; the control group received i.p. saline only at 1 ml(-1)volume. The effect of multiple doses of ginseng on bile volume and biliary composition was also studied. Ginseng was given in the higher dose of 100 mg kg(-1) (1 ml(-1), i.p.) every 12 hours for 2 days. Bile was collected in 15 min fractions for 90 min. Bile flow (bile-pancreatic juice), biliary excretion of total proteins, cholesterol and total lipids were measured. The single administration of different doses (25, 50 and 100 mg kg (-1)) of ginseng reduced basal bile secretion in a dose-dependent manner. Single-dose administration of ginseng at 100 mg kg(-1) caused 32.9% reduction in basal bile flow. Meanwhile, mean basal bile flow was reduced by 15.1% in rats treated with multiple doses of ginseng at 100 mg kg(-1) for two days. Biliary protein concentrations were significantly increased after single- or multiple-dose administration of ginseng, but protein output was only significantly increased (33%) in rats treated with ginseng (100 mg kg(-1)) twice a day for 2 days. Biliary total lipids and cholesterol concentration and outputs were significantly reduced after single or multiple administration of ginseng. In conclusion, administration of ginseng in the rat resulted in a reduction of bile flow and in bile secretion of total lipids and cholesterol, while it increased the secretion of proteins in a dose-dependent manner. The precise mechanisms underlying these effects remain to be elucidated. The findings indicate the need for clinical trials for the effect of this herb on bile composition and flow in man in view of a possible modulatory effect for the herb on gallstone formation.