Enhancement of fatty acid and cholesterol synthesis accompanied by enhanced biliary but not very-low-density lipoprotein lipid secretion following sustained pravastatin blockade of hydroxymethyl glutaryl coenzyme A reductase in rat liver.

A 3-week treatment of rats with pravastatin (PV) augmented biliary cholesterol and phospholipid output 3.6- and 2.2-fold over controls, while bile acid (BA) output and kinetics were unchanged. No major changes were detected in hepatic and serum cholesterol concentrations despite the PV inhibitory property on hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase. To evaluate the mechanisms of this adaptive phenomenon, several parameters of hepatic lipid homeostasis were assessed. Biliary cholesterol changes could not be attributed to an increased influx of lipoprotein cholesterol to the liver and bile. Hepatic low-density lipoprotein (LDL) receptor content, as inferred from Western blot analysis, was unchanged, as was the biliary excretion of labeled cholesterol derived from chylomicron remnants. In vivo 3H2O-incorporation studies showed an 80% increase in hepatic cholesterol synthesis, evidence for bypass of the PV block. Remarkably, fatty acid synthesis was also stimulated twofold, providing substrate for hepatic triglycerides, which were slightly enhanced. However, serum triglycerides decreased 52% associated with a 22% decrease in hepatic very-low-density lipoprotein (VLDL) secretion. Thus, the biochemical adaptation following PV treatment produces complex alterations in hepatic lipid metabolism. An enhanced supply of newly synthesized cholesterol and fatty acids in association with a limited VLDL secretion rate augments the biliary lipid secretion pathway in this experimental model.     

Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones

BACKGROUND AND AIMS: There is limited information available on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on hepatic and biliary cholesterol metabolism in patients with gallstones. The aims of this study were to determine the effect of simvastatin on the regulatory elements of cholesterol metabolism that determine the concentrations of cholesterol in plasma and bile. METHODS: Thirty-one gallstone patients were enrolled in the study; 17 were treated with 20 mg simvastatin daily for 3 weeks prior to cholecystectomy and 14 served as controls. Samples of blood, liver, gall-bladder bile and bile from the common bile duct (CBD) were collected and analysed. RESULTS: The plasma cholesterol (-30%), triacylglycerol (-23%) and low-density lipoprotein (LDL) cholesterol (-42%) concentrations were significantly lowered by simvastatin treatment, as was the plasma lathosterol: cholesterol (-70%), which reflects whole-body cholesterol synthesis. Despite these changes, the hepatic LDL receptor protein and LDL receptor activity in circulating mononuclear cells were similar in both groups. There were no differences in the plasma phytosterol: cholesterol, which reflects the intestinal cholesterol absorption capacity or in the activity of hepatic acyl-coenzyme A: cholesterol acyltransferase. There were however, lower cholesterol concentrations in CBD (-68%) and gall bladder (-41%) bile, and decreased lithogenic (-47%) and bile acid hydrophobicity (-22%) indices of CBD bile in the simvastatin group. CONCLUSIONS: These data indicate that simvastatin reduced plasma and biliary cholesterol levels primarily by reducing cholesterol synthesis. The reduction in CBD bile lithogenicity and bile acid hydrophobicity by simvastatin suggests that this agent may be useful for people who have early stages of cholesterol gallstone development and in whom a choleretic effect is required.     

Reduction in intestinal cholesterol absorption by various food components: Mechanisms and implications

A number of different food components are known to reduce plasma and LDL-cholesterol levels by affecting intestinal cholesterol absorption. They include: soluble fibers, phytosterols, saponins, phospholipids, soy protein and stearic acid. These compounds inhibit cholesterol absorption by affecting cholesterol solubilization in the intestinal lumen, interfering with diffusion of luminal cholesterol to the gut epithelium and/or inhibiting molecular mechanisms responsible for cholesterol uptake by the enterocyte. Cholesterol content of intestinal chylomicrons is subsequently reduced, less cholesterol is transported to the liver within chylomicron remnants, hepatic LDL-receptor activity is increased and plasma levels of LDL-cholesterol are decreased. Reduced hepatic VLDL production and less conversion of VLDL to LDL also contribute to lower LDL levels. Certain food components may also affect intestinal bile acid metabolism. Further investigation of the way in which these functional ingredients affect intestinal lipid metabolism will facilitate their use and application as cardiovascular nutraceuticals.     

Lipids and lipid-activated vitamins in chronic cholestatic diseases

Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangiopathy are cholestatic liver diseases of unknown cause. Destruction of small to medium bile ducts (in primary biliary cirrhosis and autoimmune cholangiopathy) and large bile ducts (in primary sclerosing cholangitis) leads to progressive cholestasis, liver failure and end-stage liver disease. A variety of abnormalities in lipid metabolism have been described in primary biliary cirrhosis, and range from alterations in serum lipid levels and lipoprotein subsets to deranged metabolism of cholesterol. Progressive cholestasis and, consequently, decreased small intestinal bile acid concentrations in these cholestatic liver disease can also lead to impaired absorption of fats and fat-soluble vitamins, resulting in steatorrhea and deficiencies in vitamins A, D, E, and K. This article focuses on abnormalities in lipid metabolism in primary biliary cirrhosis and primary sclerosing cholangitis, and on lipid-activated vitamin deficiencies in these disorders.     

Biliary lipid secretion in chronic cholestatic liver disease.

Biliary lipid secretion rates, faecal steroids, and serum lipids were studied in patients with chronic cholestatic liver disease mainly primary biliary cirrhosis. The biliary secretion of cholesterol, bile acids, and phospholipids was markedly decreased as compared with those in the control group and in general correlated negatively with the serum cholesterol and triglyceride values. The molar percentage of cholesterol was increased in the hepatic bile. This suggests that, in cholestatic liver disease, in contrast with the normal state, the hapatic bile may be supersaturated postprandially. Faecal bile acids and neutral sterols of cholesterol origin were decreased proportionately to the corresponding biliary lipid secretion rates. In fact, both biliary and faecal steroid outputs were only about a half or less than those in the controls, indicating that the fractional absorption was not changed but absolute absorption and faecal steroid excretion were low in patients with chronic cholestatic liver disease. Thus, despite low cholesterol and bile acid absorption, cholesterol and bile acid synthesis is low. A negative correlation between faecal steroids and serum cholesterol suggests that the high serum cholesterol level contributed to regulation of cholesterol synthesis.     

Overexpression of the cholesterol-binding protein MLN64 induces liver damage in the mouse

AIM: To examine the in vivo phenotype associated with hepatic metastatic lymph node 64 (MLN64) over-expression. METHODS: Recombinant-adenovirus-mediated MLN64 gene transfer was used to overexpress MLN64 in the livers of C57BL/6 mice. We measured the effects of MLN64 overexpression on hepatic cholesterol content, bile flow, biliary lipid secretion and apoptosis markers. For in vitro studies cultured CHO cells with transient MLN64 overexpression were utilized and apoptosis by TUNEL assay was measured. RESULTS: Livers from Ad.MLN64-infected mice exhibited early onset of liver damage and apoptosis. This response correlated with increases in liver cholesterol content and biliary bile acid concentration, and impaired bile flow. We investigated whether liver MLN64 expression could be modulated in a murine model of hepatic injury. We found increased hepatic MLN64 mRNA and protein levels in mice with chenodeoxycholic acid-induced liver damage. In addition, cultured CHO cells with transient MLN64 overexpression showed increased apoptosis. CONCLUSION: In summary, hepatic MLN64 over- expression induced damage and apoptosis in murinelivers and altered cholesterol metabolism. Further studies are required to elucidate the relevance of these fi ndings under physiologic and disease conditions.     

Biliary lipid secretion,bile acid metabolism,and gallstone formation are not impaired in hepatic lipase-deficient mice

Whereas hepatic lipase (HL) has been implicated in lipoprotein metabolism and atherosclerosis, its role in controlling biliary lipid physiology has not been reported. This work characterizes plasma lipoprotein cholesterol, hepatic cholesterol content, bile acid metabolism, biliary cholesterol secretion, and gallstone formation in HL-deficient mice and C57BL/6 controls fed standard chow, a cholesterol-supplemented diet, or a lithogenic diet. Compared with C57BL/6 controls, HL knockout mice exhibited increased basal plasma high-density lipoprotein (HDL) cholesterol as well as reduced cholesterol levels transported in large lipoproteins in response to cholesterol-enriched diets. Hepatic cholesterol content and biliary cholesterol secretion of chow-fed HL knockout and wild-type mice were not different and increased similarly in both strains after feeding dietary cholesterol or a lithogenic diet. There were no differences in biliary bile acid secretion, bile acid pool size and composition, or fecal bile acid excretion between HL-deficient and control mice. HL knockout mice had a similar prevalence of gallstone formation as compared with control mice when both strains were fed with a lithogenic diet. In conclusion, the deficiency of HL has no major impact on the availability of lipoprotein-derived hepatic cholesterol for biliary secretion; HL expression is not essential for diet-induced gallstone formation in mice.     

Inactivation of hepatic microsomal triglyceride transfer protein protects mice from diet-induced gallstones

BACKGROUND & AIMS: Microsomal triglyceride transfer protein (MTTP) is critical for the production of very-low-density lipoproteins (VLDL). The current studies were undertaken to examine the in vivo role of MTTP in hepatic cholesterol and fatty acid metabolism, as well as in biliary lipid secretion. We also tested whether MTTP plays a role in diet-induced cholelithiasis in mice. METHODS: We used mice in which Mttp had been inactivated in the liver (Mttp(Delta/Delta) mice). We measured several parameters of cholesterol metabolism, fatty acid synthesis, and biliary lipid levels in mice fed a normal or a lithogenic diet. We also assessed the incidence of diet-associated gallstones. RESULTS: Hepatic Mttp inactivation markedly decreased plasma triglyceride and cholesterol levels and increased biliary cholesterol and bile acid output. Hepatic cholesterogenesis and fatty acid synthesis were significantly decreased in Mttp(Delta/Delta) mice compared with control mice. The incidence of gallstones decreased from 90% in control mice to 33% in Mttp(Delta/Delta) mice after 8 weeks of a lithogenic diet (P < .0001). The mechanism of the protective effect appears to be increased biliary phospholipid output in Mttp(Delta/Delta) mice, leading to significant unsaturation of gallbladder bile. CONCLUSIONS: These results indicate that modulation of Mttp expression in the liver affects hepatic lipid synthesis and storage as well as biliary lipid secretion. Our findings further indicate that inhibition of hepatic MTTP activity decreases the risk of experimental cholelithiasis by favoring phospholipid output into the bile.     

A biphasic response of hepatobiliary cholesterol metabolism to dietary fat at the onset of obesity in the mouse

Human obesity is associated with abnormal hepatic cholesterol homeostasis and resistance to leptin action. Because leptin administration to rodents promotes the biliary elimination of plasma cholesterol, this study was designed to elucidate a pathophysiological role for leptin during the development of obesity. We fed mice diets containing high or low saturated fat contents. Before and after the onset of obesity, we measured downstream targets of leptin action and evaluated plasma, hepatic, and biliary cholesterol metabolism. Although not obese at 28 days, mice fed a high fat diet became hyperleptinemic. Sensitivity to leptin was evidenced by downregulation of both hepatic stearoyl CoA desaturase-1 and fatty acid synthase. Due principally to upregulation of adenosine triphosphate-binding cassette proteins A1 and G5, plasma high density lipoprotein (HDL) cholesterol concentrations increased, as did relative secretion rates of biliary cholesterol. A smaller, more hydrophilic bile salt pool decreased intestinal cholesterol absorption. In this setting, hepatic cholesterol synthesis was downregulated, indicative of increased uptake of plasma cholesterol. After 56 days of high fat feeding, obesity was associated with leptin resistance, as evidenced by marked hyperleptinemia without downregulation of stearoyl CoA desaturase-1 or fatty acid synthase and by upregulation of hepatic cholesterol and bile salt synthesis. Hypercholesterolemia was attributable to overproduction and decreased clearance of large HDL(1) particles. In conclusion, before the onset of obesity, preserved leptin sensitivity promotes biliary elimination of endogenous cholesterol in response to dietary fat. Leptin resistance due to obesity leads to a maladaptive response whereby newly synthesized cholesterol in the liver is eliminated via bile.     

Effect of cholestyramine treatment on biliary lipid secretion rates in normolipidaemic men

This study was designed to clarify the effect of bile acid sequestrant treatment on the total biliary output rates of cholesterol, phospholipids and bile acids in man, and to correlate these changes with the alterations in plasma lipoprotein levels. For this purpose nine healthy, normolipidaemic men were treated with 16 g of cholestyramine daily over a period of 4 weeks, and the biliary secretion rates were measured by a duodenal perfusion technique. Resin therapy, which profoundly increases de novo synthesis of bile acids, resulted in a lowering of total plasma cholesterol levels, mainly due to a 35% reduction in low density lipoprotein (LDL) cholesterol, and in a 33% increase in plasma triglyceride levels, reflecting enhanced very low density lipoprotein (VLDL) triglyceride concentrations; high density lipoprotein (HDL) levels did not change. However, these lipoprotein changes did not correlate with any alterations in biliary lipid output. Total hepatic secretion rates of the biliary lipids remained generally unchanged during treatment, with a tendency towards lower cholesterol output, resulting in a lower molar percentage of cholesterol in hepatic bile, 3.4 +/- 0.4 vs. 2.9 +/- 0.2 mol %. This is probably due to an increased rate of conversion of cholesterol to bile acids in the hepatocyte. It is concluded that, in man, the liver may adapt well to changes in the enterohepatic circulation of bile acids, thereby maintaining output rates of biliary lipids at a relatively constant level.     

Modulation of bile secretion by hepatic low-density lipoprotein uptake and by chenodeoxycholic acid and ursodeoxycholic acid treatment in the hamster

The effects of both apolipoprotein B,E receptor-dependent and receptor-independent uptake of low-density lipoprotein (LDL) in the liver on bile secretion were studied in bile fistula hamsters. Three groups of animals were studied after 4 wk of feeding either a control, chenodeoxycholic acid-, or ursodeoxycholic acid-containing diet. The hepatic receptor-dependent and receptor-independent uptake of LDL was related to both bile flow and biliary lipid secretion. The correlation with bile flow and biliary lipid secretion was positive for the receptor-dependent, but negative for the receptor-independent uptake of LDL. Although the receptor-mediated LDL uptake appeared to exert a strong influence on bile acid-independent bile flow, the receptor-independent uptake showed a significant relation with biliary bile acid excretion. Differences between the two mechanisms of LDL uptake were also evident in the biliary bile acid-cholesterol coupling, which was significantly stronger during receptor-independent than during receptor-dependent uptake of LDL. The effects of LDL uptake on bile secretion were modulated by the experimentally induced changes in both the content and composition of bile acids in the enterohepatic circulation.     

Deficiency of Niemann‐Pick C1 protein protects against diet‐induced gallstone formation in mice

Background/aims: Receptor‐mediated endocytosis is a critical cellular mechanism for the uptake of lipoprotein cholesterol in the liver. Because Niemann‐Pick C1 (NPC1) protein is a key component for the intracellular distribution of cholesterol originating from lipoprotein endocytosis, it may play an important role in controlling biliary cholesterol secretion and gallstone formation induced by a lithogenic diet. Methods: We studied biliary cholesterol secretion, gallbladder lipid composition and gallstone formation in NPC1‐deficient mice fed a low‐fat lithogenic diet (1.5% cholesterol and 0.5% cholic acid) compared with control animals under the same diet. Results: The lipid secretion response to the lithogenic diet was impaired in NPC1 (?/?) mice, leading to a decreased cholesterol output and an increased hepatic cholesterol concentration compared with the lithogenic diet‐fed wild‐type mice. A decreased cholesterol saturation index was found in the gallbladder bile of NPC1 (+/?) and (?/?) mice after lithogenic diet feeding. Consequently, mice with a partial or a total deficiency of NPC1 had a drastically lower frequency of gallbladder cholesterol crystals and a reduced prevalence of gallstones. Conclusion: Hepatic NPC1 expression is an important factor for regulating the biliary secretion of diet‐derived cholesterol as well as for diet‐induced cholesterol gallstone formation in mice.     

Bile Salt Metabolism:I. The Physiology of Bile Salts

Bile salt metabolism. I. The physiology of bile salts. A. E. Cowen and C. B. Campbell, Aust. N.Z. J. Med., 1977, 7, pp. 579–586. Bile salts are synthesized in the liver from cholesterol, conjugated with glycine or taurine and secreted in bile with cholesterol and lecithin. The molar concentrations of these three lipids determine solubility of cholesterol in bile. Within the gastrointestinal lumen bile salts play an essential role in lipid absorption and fat transport. An efficient entero-hepatic circulation maintains hepatic bile salt secretion and provides a “feed-back” control of bile salt and cholesterol metabolism. Potentially hepatotoxic lithocholic acid formed in the intestinal lumen by bacterial action on chenodeoxycholic acid is sulphated in the liver thus decreasing intestinal reabsorption. The total faecal excretion of bile salts balances hepatic synthesis and represents a major catabo/ic path in cholesterol metabolism.     

Impaired absorption of cholesterol and bile acids in patients with an ileoanal anastomosis

Background—No data exist on cholesterolabsorption in patients with an ileoanal anastomosis (IAA).
Aims—To study cholesterol absorption and itseffects on cholesterol and bile acid metabolism in patients with an IAA.
Patients and methods—Cholesterol absorption, andserum, biliary, and faecal lipids were studied in 24 patients with anIAA and 20controls.
Results—Fractional cholesterol absorption wassignificantly lower in the patients (36% versus 47% in controls).Surprisingly, the calculated intestinal influx of endogenouscholesterol was reduced so that the absolute absorption of cholesterolwas decreased; elimination of cholesterol as faecal neutral steroidsremained normal. Thus, the slightly increased cholesterol synthesis was mainly due to increased faecal bile acid excretion, which, in turn, wasassociated with reduced absorption and biliary secretion of bile acids.Serum total and low density lipoprotein (LDL) cholesterol and LDLtriglycerides were lower in the patients. Molar percentage andsaturation index of biliary cholesterol were slightly higher inpatients with an IAA. Proportions of secondary bile acids in bile andfaeces were diminished, and faecal unidentified bile acids were higherin patients.
Conclusions—Cholesterol absorption issignificantly impaired in patients with an IAA, and is closely relatedto changes in serum and biliary lipids observed in these patients.

Keywords:cholesterol absorption; cholesterol synthesis; faecal bile acids; inflammatory bowel disease

     

Effects of bile acid pool composition on hepatic metabolism of cholesterol in man

This work reviews the evidence concerning the role of the bile acid pool composition in the regulation of the overall hepatic metabolism of cholesterol in man. It has been known that bile acids regulate bile secretion, biliary lipid transport and hepatic cholesterol metabolism. However, the intimate mechanisms of these regulatory functions are not well understood. Current thinking attributes most of this regulation to the size of the bile acid pool. A typical example is represented by the negative feed-back mechanism by which bile acids returning to the liver control their own synthesis. Recent evidence however tend to suggest that not only the size but also the composition contributes to the regulatory activity of the bile acid pool. Specifically the hydrophobic-hydrophilic balance of the pool, as resulting from the characteristics and the proportions of the individual bile acids present within the pool, seems to dictate most of the effects of bile acids on hepatic cholesterol metabolism. Thus abundance within the pool of hydrophobic bile acids, such as deoxycholic or chenodeoxycholic acid, seems to induce a greater biliary lipid secretion and to exert inhibition of cholesterol and bile acid synthesis whereas hydrophilic bile acids such as ursodeoxycholic acid seem to be uneffective. It follows that by changing the composition of the bile acid pool it is possible to influence the hepatic metabolism of cholesterol.     

The effect of plasma low density lipoprotein apheresis on the hepatic secretion of biliary lipids in humans

Background—The liver is a key organ in themetabolism of cholesterol in humans. It is the only organ by whichsubstantial amounts of cholesterol are excreted from the body, eitherdirectly as free cholesterol into the bile or after conversion to bile acids. The major part of cholesterol synthesis in the body occurs inthe liver. Cholesterol is also taken up by the liver from plasma lipoproteins. The relative contributions of newly synthesised cholesterol and plasma lipoprotein cholesterol to bile acid synthesis and biliary cholesterol secretion, respectively, are not known in detail.
Aims—To determine how a rapid lowering of plasmalow density lipoprotein (LDL) and very low density lipoprotein (VLDL)cholesterol influences the biliary secretion rates of cholesterol andbile acids in patients with cholesterol gallstones and complete biliary drainage. In this model with a completely interrupted enterohepatic circulation, the secretion of bile acids equals the new synthesis ofbile acids in the liver.
Patients—Eight patients with common bileduct stones of cholesterol type undergoing conventional cholecystectomyand choledocholithotomy.
Methods—At operation a balloon occludable Foleycatheter attached to a T tube was inserted into the bile duct with theballoon placed just past the distal limb of the T tube. The T tube was allowed to drain the bile externally. One week after the operation theFoley catheter balloon was inflated, creating complete biliary drainage. Twelve hours following the inflation plasma LDL apheresis wascarried out for two hours. Bile was collected for 15 minute periodsstarting one hour before the apheresis and ending two hours after itstermination. During the collection of bile, plasma lipids were analysedon several occasions.
Results—The plasma level of LDL cholesteroldecreased by 26% from (mean (SEM)) 2.19 (0.29) to 1.63 (0.17) mmol/lduring the LDL apheresis while high density lipoprotein (HDL)cholesterol in plasma was unaffected. During LDL apheresisapolipoprotein B containing lipoproteins bind to the column, causing asignificant decrease of not only plasma LDL but also of VLDLcholesterol. The secretion rate of bile acids decreased significantlyby 31% from 131 (38) to 90 (16) µmol/15 minutes (p=0.045). Theoutput of phospholipids also decreased by 19%. The biliary secretion rate of cholesterol was not, however, affected by the plasma LDL apheresis.
Conclusions—The results suggest that, inpatients with cholesterol gallstones and complete biliary drainage,lowering of plasma LDL and VLDL cholesterol reduces the biliarysecretion rate—synthesis—of bile acids without affecting the biliarysecretion rate of cholesterol.

Keywords:bile acids; biliary lipids; cholesterol; lipoproteins; plasma apheresis

     

Effects of Acute and Chronic Ethanol Intake on Bile Acid Metabolism

Ethanol has been demonstrated to cause aberrations in lipoprotein metabolism, cholesterol synthesis, biliary secretion, and bile acid synthesis. Although there is interdependency of cholesterol and bile acid metabolism, a role of ethanoMnduced lipid abnormalities in altering bile acid synthesis has not been found. The direct effects of ethanol administration on bile acid metabolism have been studied in animals and vary with the experimental design. Acutely, ethanol causes decreased bile acid secretion and synthesis, but other effects are less well defined. Chronic ethanol use in man may result in cirrhosis, a condition in which abnormalities of bile acid metabolism have been described in detail. Cholic acid synthesis and pool size are markedly depressed In advanced cirrhosis. Che-nodeoxycholic acid synthesis is effected less than cholic acid synthesis, probably because 12a-hydrox-ylase activity is markedly depressed in cirrhosis, although other steps may also be influenced such as 7a-hydroxylation of cholesterol or availability of cholesterol precursor. The deoxycholic acid pool is depressed probably because of changes in fecal flora. Despite the decrease in total bile acid pool, lithogenicity of bile is not increased in cirrhotic patients because of a concomitant decline in cholesterol and phospholipid secretion. Changes in hepatic blood flow and hepatic extraction cause an increase in plasma bile acid levels which may have clinical relevance.     

Apparent selective bile acid malabsorption as a consequence of ileal exclusion: effects on bile acid, cholesterol, and lipoprotein metabolism.

A new model has been developed to characterise the effect of a standardised ileal exclusion on bile acid, cholesterol, and lipoprotein metabolism in humans. Twelve patients treated by colectomy and ileostomy for ulcerative colitis were studied on two occasions: firstly with a conventional ileostomy and then three months afterwards with an ileal pouch operation with an ileoanal anastomosis and a protective loop ileostomy, excluding on average 95 cm of the distal ileum. The ileostomy contents were collected during 96 hours and the excretion of bile acids and cholesterol was determined using gas chromatography-mass spectrometry. Fasting blood and duodenal bile samples were collected on two consecutive days. After the exclusion of the distal ileum, both cholic and chenodeoxycholic acid excretion in the ileostomy effluent increased four to five times without any change in cholesterol excretion. Serum concentrations of lathosterol (a marker of cholesterol biosynthesis) and 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) were increased several fold. Plasma concentrations of total VLDL triglycerides were also increased whereas the concentrations of total and LDL cholesterol, and apolipoprotein B were decreased. There were no changes in biliary lipid composition or cholesterol saturation of bile. The results show that the exclusion of about 95 cm of distal ileum causes malabsorption of bile acids but apparently not of cholesterol. The bile acid malabsorption leads to increased synthesis of both bile acids and cholesterol in the liver. It is suggested that bile acids can regulate cholesterol synthesis by a mechanism independent of the effect of bile acids on cholesterol absorption. The enhanced demand for cholesterol also leads to a decrease in plasma LDL cholesterol and apolipoprotein B concentrations. The malabsorption of bile acids did not affect biliary lipid composition or cholesterol saturations of VLDL triglycerides.