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Fat Absorption and Lipid Metabolism in Cholestasis

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The liver has a central role in control of various aspects of lipid metabolism. Primarily, the liver produces bile, constituents of which are required for efficient intestinal fat absorption. Additionally, biliary secretion of cholesterol (either as such, or after metabolism in the form of bile salts) and phospholipids from the liver into the intestine is of major importance in body lipid homeostasis. The liver is the major source of plasma lipoproteins: it synthesizes apoproteins (i.e., apo A-I, apo B, apo E) that regulate many complex metabolic interconversions between lipoprotein classes, as well as lipoprotein lipid constituents such as cholesterol, triglycerides, and phospholipids. The liver is also the major site of clearance of circulating lipoproteins, which are subsequently catabolized in the hepatocytes. Additionally, the liver synthesizes enzymes (e.g., LCAT, CETP, PLTP, LPL) which are involved in lipoprotein metabolism in the plasma compartment. Finally, the liver is the site of active synthesis, metabolism, and/or oxidation of various lipid classes, including long-chain polyunsaturated fatty acids (Fig. 1).

Figure 1. The liver as a central organ in lipid metabolism.

Figure 1

The liver as a central organ in lipid metabolism.

In view of this multitude of essential functions that are in part strongly interrelated, it is evident that disturbances in bile formation in cholestatic liver disease will have a strong impact on various aspects of lipid metabolism in the body. Consequences of cholestasis, which is functionally defined as decreased or absent bile flow from the liver into the intestine, may be related to:

  1. the absence of specific bile components at their sites of action, particularly in the intestine
  2. disruption of the continuous flux of lipids from the liver into bile and intestine, resulting in accumulation of toxic and non-toxic bile components in the body, most notably in hepatocytes, with concomitant alterations in hepatocyte function.
  3. characteristic alterations in plasma lipoprotein composition associated with cholestatic liver diseases such as decreased HDL levels and the appearance of lipoprotein X.

Intestinal Lipid Absorption

Dietary Lipid Classification

Dietary fat comprises a wide array of lipid classes, which have been categorized according to the nature of their interactions with water into polar and non-polar lipids.13 Polar lipids, which are insoluble in water, are cholesteryl esters, hydrocarbons, and carotene. Polar lipids are divided into 3 subclasses; firstly, the insoluble non-swelling amphiphiles which form a thin stable monolayer in water; secondly, the insoluble swelling amphiphiles which form both stable monolayers in water as well as laminated lipid-water structures called liquid crystals; and finally, the soluble amphiphiles, which possess strong polar groups that render these molecules soluble in water at low concentrations, forming both unstable monolayers and micelles.4,5 Examples of class 1 polar lipids are triacylglycerols (TAG), diacylglycerols (DAG), non-ionized long chain fatty acids (LCFA), unesterified cholesterol and the fat soluble vitamins A, D, E, and K. Class 2 insoluble swelling amphiphiles are monoacylglycerols (MAG), ionized fatty acids (FA), and phospholipids (PL). Examples of class 3 soluble amphiphiles are sodium salts of long chain fatty acids and bile salts. The absence of biliary components during cholestasis will differentially affect solubilization and absorption of lipid classes due to their different interactions with water. In this chapter, we will concentrate on digestion, absorption, and metabolism of the main dietary lipids TAG, PC, cholesterol, and fat-soluble vitamins, under physiological and cholestatic conditions.

TAG is the major fat in human diet, contributing 90 to 95% of energy provided by dietary fat. The majority of luminal phospholipid is phosphatidylcholine (PC), which is mostly of biliary origin (10–20 g daily in humans), with a dietary contribution of 1–2 g per day.1,4

The predominant dietary sterol is cholesterol (0.5 g/day,1,4 which is mostly of animal origin, although small amounts are also present in vegetables. Beta-sitosterol is the most important plant sterol (which account for 25% of dietary sterols), but it is virtually not absorbed by humans under physiological conditions due to the activity of the intestinal half-transporters ABCG5/G8, which have recently been postulated to play a major role in efficient efflux of absorbed dietary sterols from the enterocyte into the intestinal lumen, and from the liver into the bile ducts.6,7

A specific lipid group is formed by the essential fatty acids (EFA), which are long-chain polyunsaturated fatty acids that cannot be synthesized de novo by mammalian cells and therefore must be provided by the diet. EFAs are mostly present in the diet in the form of TAG and PC. Additionally, biliary PC is an important source of intestinal EFAs since it contains up to 40 mol% of EFAs.

The fat-soluble vitamins A, D, E, and K, compounds that are required in small quantities for maintenance of normal cell and organ function, 811 are class 1 polar lipids and depend upon micellar solubilization for intestinal uptake. Absorption rates differ between vitamin species, averaging 50 to 80% for vitamins A, D, and K but only 20–30% for vitamin E.12 Additionally, there may be competition between vitamin species for intestinal absorption or transport sites,13 although minimal information is available regarding the nature and function of these sites.

The sequence of processes involved in intestinal lipid absorption can be divided into intraluminal and intracellular events.

Intraluminal Phase of Lipid Absorption

Before translocation from the intestinal lumen into the enterocytes can occur, dietary lipids must undergo a number of physicochemical alterations. This is achieved in a sequence of events called the intraluminal phase of lipid digestion and absorption, including:

  • emulsification of dietary lipid
  • lipolysis
  • solubilization (micelles, vesicles)
  • translocation of lipolytic products across the enterocyte membrane

Emulsification and Lipolysis

In humans, the first step in dietary fat digestion starts in the stomach with mechanical emulsification and partial TAG hydrolysis by gastric lipase, resulting in the lipolytic products DAG and free fatty acids. Gastric lipase does not hydrolyze PL or cholesterol ester, but its activity in the stomach accounts for 10 to 30% of TAG-lipolysis.1,2,14,15 The remaining part of TAG digestion is brought about in the duodenal lumen by pancreatic lipase, which acts mainly on the sn-1 and sn-3 position of TAG molecules, releasing 2-MAG and free fatty acids.14,16 Pancreatic lipase is abundantly present in pancreatic juice, in accordance with the clinical observation that only severe pancreatic insufficiency results in lipid malabsorption. In the presence of bile salts, pancreatic lipase requires the cofactor pancreatic co-lipase1 for adequate TAG hydrolysis, since TAG droplets covered with bile salts are not accessible to pancreatic lipase. Binding of pancreatic co-lipase to the TAG/water interface facilitates binding of pancreatic lipase.

Digestion of phospholipids occurs entirely in the duodenal lumen, predominantly by pancreatic phospholipase A2. Phospholipase A2, requiring calcium and the presence of bile salts for activation, hydrolyzes phospholipids at the sn-2 position, resulting in free fatty acids and lyso-phosphatidylcholine (lyso-PC).

Dietary cholesterol is mainly present as free cholesterol and only 10–15% as cholesterol ester. Cholesterol esters must be hydrolyzed in the duodenum by pancreatic cholesterol esterase (CE) before absorption can take place. Human cholesterol esterase (also known as carboxyl ester lipase, bile salt-stimulated lipase, monoglyceride lipase, pancreatic non-specific lipase, or human milk lipase) does not only hydrolyze cholesterol esters but also acts on TAG (sn-1, sn-2, sn-3), PL (sn-1, sn-2), and lipidic vitamin esters 17 and its activity is greatly enhanced by the presence of bile salts.

Solubilization of Lipolytic Products

For diffusion through the unstirred water layer, which separates the brush border membrane of enterocytes from the liquid luminal contents of the intestine, solubilization of lipolytic products is required. The most important function of biliary bile salts, phospholipids, and cholesterol in the intestinal lumen appears to be their ability to increase the solubility of lipolytic products in the luminal aqueous phase by formation of mixed micelles. Mixed micelles were first described by Hoffman and Borgstrom18 as disc-like aggregates of amphiphilic biliary and dietary components, which orient themselves with their hydrophobic parts to the inside of the micelles and their hydrophilic polar headgroups towards the aqueous outside. This conformation increases the solubility of FFA and MAG 100–1000-fold. 4 Mixed micelles contain bile salts (class 3 polar lipids), hydrogenated fatty acids (class 1 polar lipids), fatty acid ions (class 2 polar lipids), MAG (class 2 polar lipid), phospholipids (class 2 polar lipids), and cholesterol (class 1 polar lipid), and are about 4 nm in diameter.15

Carey and Patton19 described the co-existence of these mixed micelles in the intestinal lumen with unilamellar liquid crystalline vesicles or liposomes. They demonstrated that only when intraluminal bile salt concentrations exceed a critical micellar concentration, mixed bile salt/lipid micelles are formed. However, when bile salt concentrations are decreased, large (20–60 nm) unilamellar liquid crystalline vesicles or liposomes are formed.20,21 All classes of lipolytic products can be incorporated into disc-shaped micelles as well as liquid crystalline vesicles. Since both phases co-exist, quantification of the relative contribution of the two phases remains difficult, especially since continuous exchange of 2-MAG and FA between both structures occurs. The dissociation rate of lipolytic products from vesicles and their subsequent translocation across the enterocyte membrane appeared to be slower than dissociation rates from mixed micelles, as demonstrated by Narayan and Storch.22

The existence of liquid crystalline vesicles is thought to have specific pathophysiological consequences for lipid absorption in conditions where intraluminal bile salt concentrations are diminished, as in cholestasis. It has been demonstrated that although lipid absorption rates are slower in bile salt-deficient states, fat uptake can still occur rather efficiently. Porter et al reported on a bile fistula patient who continued to absorb up to 80% of dietary lipid, despite the obvious bile salt deficiency and the hundred-fold decreased free fatty acid concentration in the aqueous phase of the small intestinal lumen.23 Mansbach et al found similar results in patients with bile salt malabsorption, where the strong decrease in solubilized fatty acid concentration led to an only mild degree of lipid malabsorption.24 Solubilization of lipolytic products into liquid crystalline vesicles during intestinal bile-salt deficiency could explain the slower but preserved rate of lipid absorption in cholestasis.

Nishioka et al studied the importance of phospholipid/cholesterol vesicles for lipid absorption during bile deficiency (Fig. 2). Intraduodenal administration of 13C-labeled linoleic acid (LA) or palmitic acid (PA) to chronically bile-diverted rats was associated with strongly decreased plasma concentrations of 13C-LA and 13C-PA. Subsequent intraduodenal supplementation with PC-cholesterol vesicles significantly reconstituted plasma concentrations of labeled palmitic acid. However, there appeared to be a delay in plasma appearance of both lipids, since at 5h after lipid administration plasma concentrations were still increasing. These observations are in concordance with the slower dissociation and translocation rates of lipolytic products from vesicles compared to mixed micelles, as proposed by Narayan and Storch.22

Figure 2. Palmitic acid and linoleic acid absorption in bile diverted rats.

Figure 2

Palmitic acid and linoleic acid absorption in bile diverted rats.

It is important to note the lipid-class difference in the dependence on bile for solubilization and consecutive uptake of fats (Fig. 3). Their less hydrophobic nature renders (poly-)unsaturated fatty acids (PUFAs) less dependent upon bile for solubilization than the more hydrophobic saturated fatty acids, despite longer chain length. Even in complete absence of intestinal bile salts, absorption of unsaturated fatty acids has been demonstrated to be relatively well preserved (80%) compared to that of saturated shorter chain fatty acids (50%), although absorption remained significantly lower than in the presence of bile (96–98%).25

Figure 3. Saturated and unsaturated fatty acid absorption in cholestatic rats.

Figure 3

Saturated and unsaturated fatty acid absorption in cholestatic rats.

In contrast to long acyl-chain lipids, short and medium acyl-chain lipids do not depend upon the luminal presence of bile salts for adequate uptake and can directly be transferred from the intestinal lumen through the enterocytes. Medium-chain, triglyceride-based formulas are therefore widely used as energy providers in conditions where intestinal solubilization is impaired. For absorption of cholesterol and fat-soluble vitamins, however, micellar solubilization by bile salts is crucial.26


For many years, translocation of lipolytic products across the unstirred water layer and the enterocyte membrane has been assumed to occur through passive diffusion. In the past decade, reports from Stremmel, Weber, Hauser et al27,28 suggested that an active carrier-mediated process is involved in transport of FA across the intestinal brush border membrane, where a family of fatty acid binding proteins (FABP) was discovered. Many members of this family appeared to have both transport and fatty acid esterifying capacities.29,30 Stahl et al identified FATP4, abundantly present in the apical membrane of mature enterocytes, as the principal intestinal transporter of long-chain fatty acids.31

A fatty acid-transporter not specific for the enterocyte was identified by Harmon et al32 who isolated a 88-kDa membrane protein termed FAT (fatty acid transporter) which appeared to be the rat homologue of human CD36. CD36 is expressed in platelets, macrophages, and endothelial cells as well as in intestine, adipose tissue, heart, and muscle, where it mediates long-chain fatty acid uptake. Impaired CD36 function is associated with a large (60–80%) defect in fatty acid uptake in these tissues.33 Some authors have suggested interactions between different fatty acid transporters to regulate intestinal fatty acid uptake;34 however, the exact molecular mechanism by which translocation of lipolytic products occurs is still a matter of debate.

Uptake of cholesterol is highly specific, since the plant sterol β-sitosterol is poorly absorbed under physiological conditions despite its structural similarity to cholesterol. In healthy individuals, 50–60% of dietary cholesterol is taken up, whereas absorption of plant sterols is less than 1%.4,35 The half-transporters ABCG5/G8, which have been implied in the autosomal recessive disorder sitosterolemia, are thought to be responsible for efficient efflux of absorbed dietary sterols from enterocytes into the intestinal lumen, and from liver into bile,6,7 possibly with different affinities for sterol species. Sitosterolemia patients appear to have 30-fold increased plasma levels of plant sterols, as well as moderately increased cholesterol absorption and decreased biliary sterol secretion, resulting in sterol accumulation and atherosclerosis.36,37

Intracellular Phase of Lipid Absorption

After translocation across the apical membrane of the enterocyte, dietary lipids migrate to the endoplasmic reticulum. Intestinal fatty acid binding protein (I-FABP) has been implied in intracellular transport of fatty acids inside the enterocyte. However, Agellon et al demonstrated in Fabpi −/− mice that I-FABP is not essential for dietary fat absorption,38 which leaves the molecular mechanism of cellular fatty acid transfer to be elucidated.

At the cytosolic membrane of the smooth endoplasmic reticulum, re-esterification of absorbed fatty acids into TAG takes place. Two different biochemical pathways are involved in TAG resynthesis, of which the MAG pathway is the most important under physiological conditions. In the MAG pathway, 2-MAG is re-acylated to DAG and subsequently to TAG by mono-acylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase enzymes (DGAT1 and 2),39,40 respectively. The alternative route of re-esterification is the α-glycerophosphate pathway, which involves conversion of glycerol-3-phosphate via phosphatidic acid to DAG and subsequently to TAG, also mediated by DGAT. Under physiological conditions there is an abundant supply of 2-MAG and FFA during lipid absorption, and the 2-MAG route will predominate over the α-glycerophosphate route.

Newly synthesized triglycerides from both pathways are thought to be metabolically distinct: TAG from the 2-MAG route is secreted more rapidly across the basolateral membrane than TAG originated from the α-glycerophosphate route. It has been suggested that the DAG from each pathway enter into separate intracellular pools. DAG from the α-glycerophosphate route is preferentially used for de novo PC synthesis.

Absorbed cholesterol, either from biliary or dietary origin, enters the free cholesterol pool inside the enterocyte, which also contains cholesterol that originates from absorption of shed intestinal mucosal membranes and from de novo synthesis. Cholesterol is transported into the lymphatic system mainly as cholesterol ester (CE) in the neutral lipid core of chylomicrons. The enzymes involved in cholesterol esterification are the acyl-CoA cholesterol acyltransferases ACAT-2 and ACAT-1. Inhibition of ACAT activity has been found to decrease absorption of dietary cholesterol, associated with lymphatic release of aberrant apo-B containing lipoproteins devoid of cholesterol esters, containing mostly TAG in their cores.39,41

Newly synthesized TAG and CE form lipid droplets in the smooth endoplasmic reticulum (SER), where packaging occurs, mainly into lipoprotein particles called chylomicrons (CM). In the SER, the surface of these nascent chylomicrons is covered with phospholipids, cholesterol and apolipoproteins apo A-I, apo A-IV, and apo B-48. Under physiological conditions, surface coat PL of lymph chylomicrons are predominantly of biliary origin rather than of dietary sources,42 whereas chylomicron TAG FA composition closely resembles that of dietary TAG. As fat absorption and TAG resynthesis proceeds, lipoprotein particles increase in size and in number and eventually end up in vesicles filled with pre-chylomicrons which are transported towards the Golgi apparatus. Here, modification of pre-chylomicrons into mature CM, including terminal glycosylation, occurs, followed by translocation to the lateral surface of the enterocyte where CM are exocytosed into the interstitium and into the lymph. Nascent chylomicrons have diameters between 100 and 1000 nm. Mesenteric lymph ducts drain into the thoracic duct, which enters the systemic circulation at the level of the jugular vein.

In recent years, it has become appreciated that biliary phospholipid secretion is necessary for proper intestinal chylomicron assembly and thus for secretion of lipid into lymph.

Studies in rats with interruption of the enterohepatic circulation by cholestyramine feeding43 or by manipulation of bile composition by dietary means44 revealed an accumulation of lipid in enterocytes. This phenomenon was also seen by Tso in bile-diverted rats,45 where subsequent administration of bile acids could only partially reinstate lipid transport into lymph. Only after administrating biliary PC was lymphatic lipid transport fully restored.

Voshol et al demonstrated a delayed plasma triglyceride appearance after an oral lipid bolus in Mdr2−/− mice lacking biliary phospholipid secretion. This aberrant postprandial plasma TAG response was accompanied by normal fecal fat excretion and accumulation of lipid droplets in the intestinal wall, suggesting a relatively well preserved intestinal lipid uptake into enterocytes in the absence of biliary phospholipids but a delay in subsequent chylomicron secretion.46 Intestinal PC requirements for CM production might be comparable to that of the liver for VLDL secretion. In choline deficiency,47 the decreased hepatic PC synthesis results in impaired production of VLDL. Similarly, enterocytes might require biliary PC for appropriate intestinal chylomicron assembly and secretion into lymph.

Alterations in Lipid Homeostasis during Cholestasis

Lipid Malabsorption

Fat malabsorption as a consequence of disturbed bile secretion is associated with weight loss due to energy deficiency (in children additionally complicated by impaired growth and development), with fat-soluble vitamin deficiencies and with essential fatty acid deficiency.

Several compensatory mechanisms for fat malabsorption during bile deficiency have been described in animal models for cholestasis. Minich et al reported on lipid malabsorption in rats with chronic bile diversion, in which bile is absent from the intestinal lumen but no (toxic) biliary components accumulate in the body. These rats appeared to substantially compensate for their markedly decreased dietary fat absorption by strongly increasing their food ingestion. 25 Subsequent morphological examination of the small intestine revealed that both villus and crypt height were significantly increased in bile-diverted rats compared to controls.

Porter and Knoebel et al described a compensatory mechanism designated as “the absorptive reserve of the small intestine”.23,48 Under physiological conditions, only the proximal part of the intestine is involved in fat absorption. In situations where proximal fat absorption appears impaired, more distal parts can also contribute.

Minich et al also demonstrated that the amount of dietary lipid strongly affects the efficacy of lipid absorption in bile deficient states. In rats with chronic bile diversion, absorption of dietary lipid remained highly efficient when regular low-fat chow was fed (84% of ingested lipid). However, when rats were fed a high-fat diet, lipid absorption coefficients decreased to around 50%, indicating that compensatory mechanisms for lipid absorption in bile deficiency have limited capacity. 5 Detailed knowledge of different compensation mechanisms and alternative routes of lipid absorption during bile deficiency are important for developing dietary treatment strategies for nutritional deficiencies in cholestatic patients.

Fat-Soluble Vitamin Deficiency

Although great variability exists between studies in defining biochemical vitamin deficiency, many reports have indicated the existence of significantly decreased fat-soluble vitamin levels under cholestatic conditions.4951 Fat-soluble vitamins (class I polar lipids, see above) are highly dependent on intraluminal solubilization by bile acids, and lack of bile flow inevitably results in malabsorption and depletion of fat-soluble vitamin stores. The extent of deficiency appears to be highly vitamin-species specific; for example, Phillips et al49 reported biochemical deficiencies of vitamins A, D, E, and K in 34%, 13%, 2%, and 8% of PBC patients, respectively. Similar values were found by Kaplan and Kowdley et al.12,50,51

Vitamin A deficiency in chronic cholestasis can not only result from intestinal malabsorption, but hepatic secretion of retinol binding protein (RBP) may also be diminished, leading to low plasma levels of retinol and impaired delivery to target tissues such as retina and epithelial cells.8 Deficiency of vitamin K can lead to life-threatening hemorrhages due to the vitamin K dependence of clotting factors II, VII, IX, X, and proteins S and C. Biliary atresia patients have been reported to present with stroke as their first consequence of cholestasis-induced lipid malabsorption.52 Although vitamin D deficiency during lipid malabsorption can partially be circumvented by endogenous photosynthesis of vitamin D3 in the skin, many chronically ill patients are not adequately exposed to sunlight, resulting in low vitamin D and calcium levels and impaired bone mineralization.8,9 Prolonged vitamin E deficiency in cholestatic children leads to a degenerative neuromyopathy, eventually resulting in peripheral neuropathy, muscular weakness, ophthalmoplegia, and retinal dysfunction, which appears irreversible to a significant degree. The irreversibility and severity of many of the symptoms associated with fat-soluble vitamin deficiencies mandate strict monitoring and correction of vitamin status in cholestatic patients.

Essential Fatty Acid (EFA) Deficiency

EFA deficiency as a consequence of overall lipid malabsorption in cholestasis is well recognized. However, in the last decade it has become apparent that EFA deficiency in itself can impair the efficiency of lipid absorption. Levy et al observed decreased biliary bile salt secretion rates in EFA-deficient rats,53 implying impaired bile formation as a probable cause for EFAD-induced fat malabsorption. However, in a mouse model for EFA deficiency, we recently reported an increased bile flow and biliary bile salt secretion compared to EFA-sufficient controls. Additionally, lipid absorption in Mdr2−/− mice, secreting phospholipid-free bile, was equally affected by EFA deficiency as that in control mice. Thus, altered biliary phospholipid secretion as major contributor to the pathophysiological mechanism behind fat malabsorption during EFA deficiency in mice is excluded.54 Apart from an apparent species specificity in the effects of EFAD, it is concluded that fat malabsorption in EFAD mice is not due to impaired bile formation, and it is suggested that EFA deficiency affects intracellular events of dietary fat absorption occurring in the enterocyte. If true, EFA deficiency during cholestasis may further compromise dietary fat absorption.

Lipid Metabolism

During lipid absorption, the intestine releases large amounts of TAG-rich chylomicrons into the circulation. During fasting, however, the liver is the major source of TAG-rich lipoproteins by secreting VLDL. Both liver and intestine are capable of synthesizing HDL, which are secreted as nascent particles containing predominantly phospholipids and unesterified cholesterol. Another major lipoprotein, LDL, is formed in the plasma compartment as a product of VLDL catabolism. Additionally, the liver synthesizes apoproteins that are essential structural and enzymatic components of lipoproteins. Apoproteins act as cofactors for enzymes crucial for cholesterol esterification or triglyceride lipolysis. Apo A-I activates the cholesterol-esterifying enzyme LCAT, which is also synthesized in the liver. Apo C-II is required for lipoprotein lipase activation, which hydrolyzes lipoprotein triglycerides, thus converting chylomicrons into chylomicron remnants and VLDL into IDL and ultimately LDL. Apo E and apo B are crucial for receptor-mediated uptake of lipoproteins by peripheral cells, as well as for hepatic uptake of end products of lipoprotein catabolism.55,56 Lipoprotein remnant uptake by the liver, mediated by SR-B1 and hepatic lipase, provides a feedback inhibition mechanism for cholesterol homeostasis by regulating activity of HMG-CoA reductase, the key enzyme in hepatic cholesterol neosynthesis. Hepatocyte damage due to toxic accumulation of bile acids in cholestasis may disrupt synthesis of apoproteins and of other enzymes involved in lipoprotein formation and metabolism such as LCAT, CETP, and PLTP, with concomitant derangements in plasma and hepatic lipid homeostasis which will be discussed below.

Lipoprotein X in Cholestasis

Biliary excretion is the principal route for cholesterol disposal from the body (either direct or after conversion into bile acids), and cholestasis thoroughly deranges the whole body sterol balance. The well-recognized increase in plasma free cholesterol observed in cholestasis is accompanied by an equimolar elevation of plasma phospholipid.57,58 Hypercholesterolemia in cholestasis, particularly in extrahepatic forms, is accompanied by plasma appearance of an aberrant lipoprotein, LpX.59,60 Kostner and Laggner et al described LpX as a 40–100 nm bilamellar vesicle with an aqueous lumen, predominantly composed of phospholipids and free cholesterol in equimolar amounts and containing only minor amounts of TAG (3%) and cholesteryl ester (2%). 61,62 Gradient ultracentrifugation revealed that LpX is isolated in the LDL fraction,63 and contains apo C as well as albumin. Manzato et al hypothesized that LpX particles represent biliary vesicles regurgitated from liver into plasma of cholestatic subjects,58 since both LpX and bile vesicles are composed of PC and free cholesterol. The presence of apo C and albumin, as well as the observation that the cholesterol/PC ratio in LpX differs from that in bile, can be explained by plasma interactions of LpX with other lipoproteins. LpX is not readily taken up by the liver, thus LpX cholesterol does not participate in feedback inhibition of hepatic cholesterol synthesis. This could contribute to the paradox of increased hepatic cholesterol neosynthesis in hypercholesterolemia during cholestasis. Felker et al observed LpX-like vesicles within bile canaliculi of bile duct-ligated rats, indicating a biliary origin of the particle. 63,64 Oude Elferink et al demonstrated the biliary origin of LpX in bile duct ligated Mdr2-/- mice, which secrete phospholipid-free bile. In contrast to controls, bile duct ligation in Mdr2−/− mice resulted in decreased plasma cholesterol and PC concentrations and a complete absence of LpX particles, suggesting that during cholestasis, biliary lipid reflux occurs from bile into the plasma compartment.65 Bloks et al described the presence of LpX in ferrochelatase-deficient mice whose livers are not uniformly cholestatic but, instead, show enhanced bile flow and biliary bile salt secretion rates. Since LCAT activity was not impaired in these animals, the authors propose that formation of LpX is related to relative undersecretion of biliary PC and cholesterol that is observed in these animals.66 Although the exact nature of LpX formation in ferrochelatase-deficient mice remains to be established, it is evident that this aberrant particle can be formed in situations in which bile formation per se is not impaired.

HDL in Cholestasis

Apart from the increased lipid content in the LDL fraction in the form of LpX, the appearance of TAG-rich LDL and the decreased plasma VLDL concentrations, chronic cholestasis is associated with strongly decreased plasma HDL concentrations (<10%).67 The mechanism behind this may involve either an increased HDL clearance rate during cholestasis, or a decreased HDL synthesis. Recent work indicates that bile salts, accumulating in hepatocytes during cholestasis, are able to suppress apo A-I gene transcription via a negative farnesoid X receptor (FXR) response element mapped to the C-site of the apo A-I promoter.68 As HDL is partly derived from CM surface remnants, low plasma HDL levels could also result from decreased CM formation during intestinal bile deficiency, or from defective HDL formation from CM surface remnants by PLTP. 69 Upon ultracentrifugation, the HDL observed in cholestasis is in the density range of bilamellar discoidal particles, enriched in free cholesterol and phospholipid with decreased apo A-I and apo A-II contents and increased apo E, resembling so-called “nascent” HDL particles. Such particles are normally not found in the plasma compartment in considerable amounts because of rapid transformation by concerted actions of LCAT, CETP, and PLTP.

Lipoprotein-Metabolizing Enzymes in Cholestasis


Lecithin cholesterol acyl transferase (LCAT) and hepatic lipase (HL) are two of the key enzymes in lipoprotein metabolism. Both proteins are produced in the liver, but LCAT is active in the circulation at the surface of HDL, whereas hepatic lipase resides at the hepatic endothelial cell lining. LCAT, a 60-kDa glycoprotein that converts cholesterol and phosphatidylcholines into cholesteryl esters and lyso-PC, is activated by apo A-I. Its cholesterol-esterifying activity not only moves cholesterol from the HDL surface into the core and thereby promotes the flux of cholesterol from cell membranes into HDL, but it also leads to morphological changes of the HDL particle. Nascent disc-shaped HDL becomes spherical as cholesteryl esters accumulate in the HDL core. Hepatic lipase and LCAT hydrolytic activities together account for over 80% of disappearance of PC from plasma.70 Impaired hepatic synthesis of these enzymes in cholestasis may thus contribute to increased plasma PC concentrations. Both plasma cholesteryl ester as well as LCAT concentrations are decreased in cholestatic subjects, and the plasma appearance of “nascent” discoidal HDL particles is assumed to be a direct result from defective LCAT functioning. Furthermore, discoidal HDL has also been described in association with primary familial LCAT deficiency.57


Cholesteryl ester transfer protein (CETP) transfers excess cholesteryl esters from HDL to VLDL and LDL in exchange for TAG,71,72 thus participating in the so-called reverse cholesterol transport. CETP activity results in homogenous fatty acid species distribution between lipoprotein fractions. Activity of CETP is decreased 25% in cholestasis, associated with a decreased LA content of VLDL-TG and cholesteryl esters compared to those of HDL.71 Faust et al demonstrated that fatty acid absorption regulates CETP secretion in CaCo-2 cells,73,74 and several animal and human studies7578 revealed that high-fat diets can increase CETP activity. Freeman et al suggested that serum TAG levels above 1.4 mmol/l are required for significant CETP-mediated lipid exchange between LDL and VLDL.79 The mechanism for the decreased CETP activity in cholestatic subjects is not obvious because of the multiple origin of CETP synthesis (liver, intestine, adipose tissue, macrophages).80,81 However, since hepatocytes are the predominant source of CETP, impaired hepatic CETP synthesis remains a likely contributor to the decreased CETP activity in cholestasis.71


Plasma phospholipid transfer protein (PLTP) circulates bound to HDL and mediates transfer of phospholipids from apo B-containing lipoproteins into HDL, thus modulating HDL size and lipid composition. PLTP activity generates pre-beta HDL, the major acceptor of cholesterol in the reverse-cholesterol transport route. PLTP-knockout mice have been shown to have markedly reduced HDL levels due to defective transfer of phospholipids from triglyceride-rich lipoproteins into HDL.82 Liver, adipose tissue, and lung are presumably the major sources of circulating PLTP. Impaired hepatic synthesis of PLTP in cholestatic conditions can markedly reduce circulating HDL levels and additionally, due to the stimulatory effect of PLTP on CETP activity, 83 it can further deteriorate the already impaired CETP function. Recently, PLTP has been identified as an FXR target gene, 84 providing a molecular basis for reduced PLTP gene expression under cholestatic conditions.

Essential Fatty Acid (EFA) Metabolism in Cholestasis

Socha et al reported on decreased plasma arachidonic acid levels in pediatric cholestatic patients, which was attributed to impaired hepatic microsomal desaturase and/or elongase activity. 85,86 However, Minich et al recently demonstrated that conversion of [13C]linoleic acid to [13C]arachidonic acid was not significantly different in short-term, bile duct-ligated rats compared to controls. Accordingly, Δ6-desaturase activity as determined in hepatic microsomes was not altered.87 These results are in agreement with observations of de Vriese et al, who found no differences in Δ9-, Δ6-, and Δ3-desaturase activities in liver microsomes of cholestatic and non-cholestatic rats.88 Decreased net uptake of the parent EFA linoleic acid observed in cholestatic subjects appears the predominant cause of low plasma AA levels, rather than post-absorptive EFA metabolism. Yet, in rats with long-term bile duct ligation, impaired hepatic β-oxidative capacity has been reported.89

Nutritional Therapy in Cholestasis

Chronic cholestasis is frequently accompanied by nutritional deficiencies due to inadequate dietary intake, maldigestion, malabsorption and/or defective metabolism of nutrients. Additionally, requirements of energy and/or specific nutrients may be increased during cholestasis. Generally, the recommended caloric intake for patients with chronic cholestasis is 130% of recommended daily allowance, usually accomplished by dietary supplementation with glucose polymers and/or MCT oil enriched with essential fatty acid-rich oils.90,91 The enteral route is preferred but in severe chronic malabsorption, nasogastric and nocturnal feedings are often required.71

Fat-soluble vitamin deficiency is frequently present, particularly in cholestatic children, for which adequate and rapid correction is required. For treatment of vitamin D deficiency, a regimen of oral 25-OHD is recommended, at a dose of 2–4 μg/kg/d in children and 50–100 μg in adults, with regular measurements of cholecalciferol levels in plasma to exclude development of toxicity. Vitamin K supplements of 2.5–5 mg 2–7 times a week are currently recommended as prophylaxis for all children with chronic cholestasis.8,9 Most cholestatic children absorb the phylloquinone form of vitamin K adequately. In adults, vitamin K supplements are only recommended when blood tests suggest deficiency. For correction of vitamin E deficiency, standard oral forms of vitamin E (α-tocopherol, α-tocopheryl acetate, α-tocopheryl succinate) are recommended at doses starting from 10–25 IU/kg/d increasing to 100–200 IU/kg/d.

In situations where normalization of plasma vitamin E levels is not reached, a water-soluble form of vitamin E called d-α-tocopheryl polyethylene glycol-1000 succinate (TPGS) has been shown to markedly improve vitamin E status in cholestatic patients.92 Argao et al demonstrated that absorption of other fat-soluble vitamins is greatly enhanced by simultaneous administration with TPGS. 93 Recommended dosage of vitamin A in chronic cholestasis is 10,000 IU if given with TPGS. 92 Irrespective of the form of vitamin supplementation that is chosen, plasma vitamin levels should be carefully monitored to avoid excessive serum levels and toxicity.


Cholestatic liver disease can disturb many aspects of lipid absorption and metabolism. Accumulation of potentially toxic bile components in hepatocytes due to disruption of the flux of bile from the liver into the gut can damage hepatocytes, resulting in impaired synthetic function and decreased production of enzymes involved in lipoprotein metabolism. Also, lipoprotein secretion appears to be disturbed during cholestasis, reflected by decreased HDL levels and appearance of the aberrant lipoprotein X in plasma. The absence of biliary components from the intestinal lumen during cholestasis can strongly impair uptake of dietary fat and fat-soluble vitamins, resulting in a variety of nutritional deficiencies. Prolonged survival of patients with chronic cholestasis in the past decades will require critical evaluation of nutrient deficiencies and adequate treatment strategies in order to prevent permanent sequelae and to improve quality of life.


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