Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A deficiency in microsomal triglyceride transfer protein (MTP) causes the human lipoprotein deficiency syndrome abetalipoproteinemia. However, the role of MTP in the assembly and secretion of VLDL in the liver is not precisely understood. It is not clear, for instance, whether MTP is required to move the bulk of triglycerides into the lumen of the endoplasmic reticulum (ER) during the assembly of VLDL particles. To define MTP's role in hepatic lipoprotein assembly, we recently knocked out the mouse MTP gene (Mttp). Unfortunately, achieving our objective was thwarted by a lethal embryonic phenotype. In this study, we produced mice harboring a "floxed" Mttp allele and then used Cre-mediated recombination to generate liver-specific Mttp knockout mice. Inactivating the Mttp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and HDL cholesterol levels. The Mttp inactivation lowered apo B-100 levels in the plasma by >95% but reduced plasma apo B-48 levels by only approximately 20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wild-type mouse livers revealed numerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (ER and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and there were numerous cytosolic fat droplets. We conclude that MTP is essential for transferring the bulk of triglycerides into the lumen of the ER for VLDL assembly and is required for the secretion of apo B-100 from the liver.
 ...
PMID:Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. 1022 72

We determined the relationship between microsomal triglyceride transfer protein (MTP) (activity, mass, and mRNA) and liver triglyceride concentration in 16 dairy cows (13 multiparous and three primiparous) from 27 d before expected calving (d -27) to 35 d postpartum (d 35), the time period when fatty liver is most likely to develop. In addition, dry matter intake, plasma nonesterified fatty acids (NEFA), and plasma glucose were monitored. There were no significant parity x time interactions. Dry matter intake, plasma NEFA, plasma glucose, and liver triglyceride were significantly affected by day of sampling. Dry matter intake was 10.7, 8.0, and 19.5 kg/d on d -27, 2, and 35, respectively. Plasma NEFA concentration was higher on d 2 (1113 microEq/L) compared with d -27 (201 microEq/L) and 35 (358 microEq/L). Plasma glucose concentration was 63.3, 54.3, and 57.8 mg/dl on d -27, 2, and 35, respectively. Hepatic triglyceride (TG) concentration increased from 1.8 to 11.8% liver TG (DM basis) on d -27 and 2, respectively. There was no difference between hepatic triglyceride concentration on d 2 and 35. There was a significant effect of day of sampling on hepatic MTP activity and mRNA. Hepatic MTP activity decreased from 2.08 to 1.79 nmole triolein transferred/ h per mg of microsomal protein on d -27 and 2, respectively, and increased from 1.79 to 2.17 nmole triolein transferred/h per mg of microsomal protein on d 2 and 35, respectively. Hepatic MTP mRNA increased from d -27 to 2 and remained elevated from d 2 to 35. There was no effect of day of sampling on MTP mass. There were no significant correlations between hepatic MTP activity, mass, or mRNA with either liver TG or plasma NEFA on any of the sampling days. The cause of a decrease in hepatic MTP activity and increase in mRNA on d 2 is unknown. However, the lack of correlation between MTP activity, mass, or mRNA with either liver TG or plasma NEFA on d 2 postpartum suggests that MTP probably does not play a role in the etiology of fatty liver that occurs in dairy cows at calving.
 ...
PMID:Changes in hepatic microsomal triglyceride transfer protein and triglyceride in periparturient dairy cattle. 1104 65

Recently, we generated mice lacking microsomal triglyceride transfer protein (MTP) in the liver (Mttp(Delta/Delta)) and demonstrated that very low density lipoprotein secretion from hepatocytes was almost completely blocked. The blockade in lipoprotein production was accompanied by mild to moderate hepatic steatosis, but the mice appeared healthy. Although hepatic MTP deficiency appeared to be innocuous, we hypothesized that a blockade in very low density lipoprotein secretion and the accompanying steatosis might increase the sensitivity of Mttp(Delta/Delta) livers to additional hepatic insults. To address this issue, we compared the susceptibility of Mttp(Delta/Delta) mice and Mttp(flox/flox) controls to hepatic injury from Escherichia coli lipopolysaccharides, concanavalin A, and Pseudomonas aeruginosa exotoxin A. At baseline, neither the Mttp(Delta/Delta) nor the Mttp(flox/flox) mice had elevated serum transaminases or histologic evidence of hepatic inflammation. After the administration of the toxins, however, the Mttp(Delta/Delta) mice manifested higher levels of transaminases and, unlike the Mttp(flox/flox) mice, developed histologic evidence of hepatic inflammation. The toxic challenge induced tumor necrosis factor-alpha to a similar extent in Mttp(Delta/Delta) and Mttp(flox/flox) mice, but other parameters of injury (e.g. chemokine transcript levels and lipid peroxides) were disproportionately increased in the Mttp(Delta/Delta) mice. Our results suggest that blocking lipoprotein secretion in the liver may increase the susceptibility of the liver to certain toxic challenges.
 ...
PMID:Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury. 1173 87

Liver steatosis, which involves accumulation of intracytoplasmic lipid droplets, is characteristic of hepatitis C virus (HCV) infection. By use of an in vivo transgenic murine model, we demonstrate that hepatic overexpression of HCV core protein interferes with the hepatic assembly and secretion of triglyceride-rich very low density lipoproteins (VLDL). Core expression led to reduction in microsomal triglyceride transfer protein (MTP) activity and in the particle size of nascent hepatic VLDL without affecting accumulation of MTP and protein disulfide isomerase. Hepatic human apolipoprotein AII (apo AII) expression in double-core/apo AII transgenic mice diminished intrahepatic core protein accumulation and abrogated its effects on VLDL production. Apo AII and HCV core colocalized in human HCV-infected liver biopsies, thus testifying to the relevance of this interaction in productive HCV infection. Our results lead us to propose a new pathophysiological animal model for induction of viral-related steatosis whereby the core protein of HCV targets microsomal triglyceride transfer protein activity and modifies hepatic VLDL assembly and secretion.
 ...
PMID:Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. 1181 66

Type 2 diabetes in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA) fluxes, decreased FA oxidation, and hepatic steatosis. In this condition, VLDL production is increased and resistant to suppressive effects of insulin. The relationships between hepatic FA metabolism, steatosis, and VLDL production are incompletely understood. We investigated VLDL-triglyceride and -apolipoprotein (apo)-B production in relation to DNL and insulin sensitivity in female ob/ob mice. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob/ob mice compared with lean controls. Hepatic DNL was increased approximately 10-fold in ob/ob mice, whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and -apoB100 production were similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and -apoB100 production rates by approximately 60% and approximately 75%, respectively, in lean mice but only by approximately 20% and approximately 20%, respectively, in ob/ob mice. No differences in hepatic expression of genes encoding apoB and microsomal triglyceride transfer protein were found. Hepatic expression and protein phosphorylation of insulin receptor and insulin receptor substrate isoforms were reduced in ob/ob mice. Thus, strongly induced hepatic DNL is not associated with increased VLDL production in ob/ob mice, possibly related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob/ob mice, presumably because of impaired insulin signaling.
 ...
PMID:Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin. 1271 36

The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.
 ...
PMID:[New antilipemics: prospects]. 1282 7

Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder either linked or not linked to apolipoprotein (apo) B gene. Abetalipoproteinemia (ABL) is a recessive disorder due to mutations of microsomal triglyceride transfer protein (MTP) gene. We investigated a patient with apparently recessive hypobetalipoproteinemia consistent with symptomatic heterozygous FHBL or a "mild" form of ABL. The proband had fatty liver associated with LDL-cholesterol (LDL-C) and apo B levels <5th percentile but no truncated apo B forms detectable in plasma. MTP gene sequence revealed that he was a carrier of the I128T polymorphism and an unreported amino acid substitution (V168I) unlikely to be the cause of hypobetalipoproteinemia. Apo B gene sequence showed that he was heterozygous for two single base substitutions in exon 9 and 22 resulting in a nonsense (Q294X) and a missense (R1101H) mutation, respectively. Neither of his parents carried the Q294X; his father and paternal grandmother carried the R1101H mutation. Analysis of polymorphic genetic markers excluded non-paternity. In conclusion, the proband has a "de novo" mutation of apo B gene resulting in a short truncated apo B form (apo B-6.46). Sporadic cases of FHBL with an apparently recessive transmission may be caused by "de novo" mutations of apo B gene.
 ...
PMID:Hypobetalipoproteinemia with an apparently recessive inheritance due to a "de novo" mutation of apolipoprotein B. 1473 81

Limited secretion of very low density lipoproteins (VLDL) in dairy cows is strongly related to fatty liver and other metabolic disorders in the early postpartum. Currently, there is limited information on which roles apolipoprotein B(100) (ApoB(100)), apolipoprotein E (ApoE), and microsomal triglyceride transfer protein (MTP) play in that VLDL limitation. To our knowledge, no studies have simultaneously measured ApoB(100), ApoE, and MTP mRNA in periparturient dairy cows. Therefore, a trial was conducted to assess liver gene expression of these proteins in transition dairy cows and to evaluate the relationships between their expression and metabolic status. Eight multiparous Holstein cows were monitored during the transition period. To evaluate metabolic and nutritional status, body condition score was registered, and plasma indexes of energy metabolism and VLDL were determined from 35 d before to 35 d after calving. Liver biopsies were performed on d -35, 3, and 35 relative to day of calving, and gene expression of ApoB(100), ApoE, and MTP were determined on liver tissue. Body condition, plasma glucose and VLDL decreased, and plasma NEFA and BHBA increased after calving. Compared with values of d -35, on d 3 after calving the ApoB(100) mRNA synthesis was lower, whereas MTP and ApoE mRNA abundance were higher. Negative correlation (r = -0.57) between plasma NEFA concentration and ApoB(100) mRNA abundance, and positive correlation between ApoB(100) mRNA abundance and plasma cholesterol (r = 0.65) and plasma albumins (r = 0.52) were detected at 3 d postpartum. Data on changes of gene expression of the 3 main proteins involved in the regulation of synthesis and secretion of VLDL in the liver suggest that decreased mRNA for ApoB(100) may be consistent with decreased synthesis and/or secretion of VLDL from liver during the periparturient period.
 ...
PMID:Abundance of mRNA of apolipoprotein b100, apolipoprotein e, and microsomal triglyceride transfer protein in liver from periparturient dairy cows. 1537 48

We studied the roles of hepatitis C virus (HCV) core protein in hepatic steatosis and changes in hepatic lipid metabolism. HCV core protein expression plasmid was transfected in HepG2. Triacylglyceride (TG) and mRNA level associated with lipid metabolism were measured. Male C57BL/6 mice were infected with HCV core recombinant adenovirus and used for lipids and mRNA studies. In HCV core protein-expressing cells, peroxisome proliferator-activated receptor (PPAR)alpha, multidrug resistance protein (MDR) 3, and microsomal triglyceride transfer protein (MTP) were down-regulated 48 hr after transfection. In HCV core protein-expressing mice, hepatic TG content and hepatic thiobarbituric acid-reactive substances increased. PPARalpha, MDR2, acyl-CoA oxidase (AOX), and carnitine palmitoyl transferase-1 (CPT-1) were down-regulated. HCV core protein down-regulated lipid metabolism-associated gene expression, Mdr2, CPT, and AOX, accompanied by down-regulation of PPARalpha. There findings may contribute to the understanding of HCV-related steatosis, induction of reactive oxygen species, and carcinogenesis.
 ...
PMID:Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. 1604 88

Unlike the livers of humans and mice, and most hepatoma cells, which accumulate triglycerides when treated with microsomal triglyceride transfer protein (MTP) inhibitors, L35 rat hepatoma cells do not express MTP and cannot secrete very low density lipoprotein (VLDL), yet they do not accumulate triglyceride. In these studies we show that transcriptional co-repression of the two lipid transfer proteins, liver fatty acid-binding protein (L-FABP) and MTP, which cooperatively shunt fatty acids into de novo synthesized glycerolipids and the transfer of lipids into VLDL, respectively, act together to maintain hepatic lipid homeostasis. FAO rat hepatoma cells express L-FABP and MTP and demonstrate the ability to assemble and secrete VLDL. In contrast, L35 cells, derived as a single cell clone from FAO cells, do not express L-FABP or MTP nor do they assemble and secrete VLDL. We used these hepatoma cells to elucidate how a conserved DR1 promoter element present in the promoters of L-FABP and MTP affects transcription, expression, and VLDL production. In FAO cells, the DR1 elements of both L-FABP and MTP promoters are occupied by peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (RXRalpha), with which PGC-1beta activates transcription. In contrast, in L35 cells the DR1 elements of both L-FABP and MTP promoters are occupied by chicken ovalbumin upstream promoter transcription factor II, and transcription is diminished. The combined findings indicate that peroxisome proliferator-activated receptor alpha-RXRalpha and PGC-1beta coordinately up-regulate L-FABP and MTP expression, by competing with chicken ovalbumin upstream promoter transcription factor II for the DR1 sites in the proximal promoters of each gene. Additional studies show that ablation of L-FABP prevents hepatic steatosis caused by treating mice with an MTP inhibitor. Our findings show that reducing both L-FABP and MTP is an effective means to reduce VLDL secretion without causing hepatic steatosis.
 ...
PMID:Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis. 1695 Jul 64


1 2 3 4 5 6 7 8 9 Next >>