Altered lipid metabolism in apolipoprotein E–deficient mice does not affect cholesterol balance across the liver

✍ Scribed by F Kuipers; J M van Ree; M H Hofker; H Wolters; G I Veld; R Havinga; R J Vonk; H M Princen; L M Havekes

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 514 KB
• Volume: 24
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510240138

✦ Synopsis

Apolipoprotein E (apoE) 1 is an important constituent of Adaptation of cholesterol and bile acid synthesis and various plasma lipoproteins, including very low-density lipoof biliary cholesterol secretion represent key metabolic proteins, chylomicrons and their remnants, and essential for responses to maintain cholesterol homeostasis and have uptake of these lipoproteins by the low-density lipoprotein been suggested to be influenced by apolipoprotein E (LDL) (B, E) receptor and the putative chylomicron remnant (apoE) phenotype in humans. We have investigated hereceptor. In addition, a secretion-recapture role for apoE patic metabolism and secretion of cholesterol into bile has been proposed, 3 in which apoE is secreted by hepatocytes in homozygous apoE-deficient (apoE 0/0) mice fed norinto Disse's space to interact with lipoproteins, thereby enmal lab chow. Plasma cholesterol levels were 10 times hancing their uptake by the liver cells. Apart from its role higher in apoE (0/0) mice than in controls (///); triacylin plasma lipoprotein metabolism, apoE may play a role in glycerol levels were only minimally affected. Hepatic cholesterol (/56%) and triacylglycerol (/232%) contents redistribution of lipids within the brain 4,5 and modulate inwere significantly increased in apoE (0/0) mice, tracellular lipid metabolism. 6 whereas those of cholesteryl ester and of phospholipids Human apoE is a polymorphic protein as a result of the were similar in both groups. Lipid accumulated predomexistence of multiple alleles at a single gene locus, designated inantly in periportal areas of apoE (0/0) livers. Hepatic APOE*2, APOE*3, and APOE*4. As a consequence, six dif-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG ferent phenotypes can be found in the general population, CoA reductase) messenger RNA (mRNA) level and aci.e., E2E2, E3E3, E4E4, E2E3, E2E4, and E3E4. Population tivity were reduced by 45% and 50%, respectively, in studies indicate that APOE*3 represents the wild-type al-apoE (0/0) mice. In contrast, plasma lathosterol/cholele. 7 ApoE deficiency in humans has been described in a lesterol ratios, indicative for whole-body cholesterol limited number of patients and was found to result in sesynthesis, were fourfold increased in these mice. Acylverely elevated plasma cholesterol levels. Several mutant coenzyme A:cholesterol acyltransferase (ACAT) activforms of apoE, including apoE2, lead to impaired clearance ity was similar in livers of both groups. Despite the of remnant particles by the liver. Uptake of apoE-containing marked changes in hepatic cholesterol metabolism, particles appears to be of importance for the regulation of neither hepatic bile acid synthesis, bile acid pool size hepatic cholesterol metabolism and removal of the sterol via and composition, nor hepatic cholesterol 7a-hydroxythe bile in humans. The latter can take place in the form of lase and sterol 27-hydroxylase mRNA levels differed free cholesterol or after its conversion to bile acid. Kesa ¨niemi between apoE (0/0) and (///) mice. In addition, biliary et al. found that, in normolipidemic subjects, cholesterol cholesterol secretion was unaffected in the knock-out and bile acid synthesis decreased with apoE phenotype in mice. Our results show that lack of apoE leads to the order E2 ú E3 ú E4, whereas the opposite was found for marked changes in hepatic cholesterol metabolism intestinal cholesterol absorption. Kempen et al. 11 reported without altering cholesterol balance across the liver. elevated plasma levels of lathosterol, considered an indicator The data are compatible with increased peripheral of whole-body cholesterol synthesis in humans, in type cholesterol biosynthesis in apoE-deficient mice. (HEP-III hyperlipoproteinemia but, in contrast to Kesa ¨niemi et ATOLOGY 1996;24:241-247.) al., 10 not in normolipidemics with the E2/E2 phenotype. Angelin et al. 14 showed that the apoE2/2 phenotype is associated with increased bile acid formation both in normo and hyperlipidemics and suggested this to be a metabolic adaptation to increased hepatic cholesterol synthesis caused by im-Abbreviations: apoE, apolipoprotein E; LDL, low-density lipoprotein; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; ACAT, acyl-CoA:cholesterol acyltransferase; mRNA, paired remnant uptake. Finally, Juvonen et al. 15 reported messenger RNA; cDNA, complementary DNA; GAPDH, glyceraldehyde-3-phosphate dehythat, in normolipidemic gallstone patients, the content of chodrogenase.