A number of agents that produce liver injury also cause the accumulation of an abnormal amount of fat, predominantly triglycerides (TGs) in the parenchymal cells. Fatty liver (FL) is the result of an hepatocyte imbalance between the rate of synthesis and output of TGs into the plasma. TGs are not secreted as such, but combined with a glycoprotein moiety, and particularly with the very low density lipoproteins (VLDLs). This fraction is involved in the transport of hepatic TGs to extrahepatic tissues. FL can be induced by either acute or chronic administration of ethanol (EtOH), and/or several haloalkanes (carbon tetrachloride, CCl4; 1.2-dichloroethane, DCE; 1.1.2.2-tetrachloroethane, TTCE), both in laboratory animals and in man. Since the pathogenesis of this disease is a crucial problem, as yet undefined, the purpose of this article is to summarize the studies which have unraveled some of the mechanisms involved in FL, particularly the role played by impaired lipoglycoproteins (LGP) metabolism in rat liver.An important element in the pathogenesis of EtOH- and haloalkanes-induced FL is the impairment of hepatic secretion of VLDLs, which occurs soon after poisoning. Various steps of the secretory pathway are probably involved in the expression of such damage. The intoxication of rats with these xenobiotics leads to an early impairment of the hepatocyte system responsible for terminal glycosylation and maturation of LGP at the level of three different subfractions (F1, F2 and F3) of purified Golgi apparatus (GA). The earliest functional change is a block of LGP transit through the GA cisternae and vesicles, both in isolated hepatocyte model and in the whole animal. The glycosylation of LGP is a multistep process which starts in the rough endoplasmic reticulum (RER), and comes to its end in the GA. Dolichols (Dol) are a family of long-chain polyisoprenoid alcohols, present either as neutral free-Dol and dolichyl-phosphate (Dol-P). The latter acts as a glycosyl carrier across the RER membranes in the initial steps of LGP biosynthesis. Nearly all the other reactions occur in GA, where free-Dol have a role either in terminal LGP processing or in their secretion into the blood stream. Several investigations indicated that both EtOH and haloalkanes (CCl4, DCE, and TTCE) may selectively and precociously impair the total microsomes (TM) and GA pool of Dol, particularly in F1. Lipid peroxidation appears to be the fundamental mechanism involved.Such results, obtained in several works, point out a key role played in FL by selective impairment of MT and GA processes which provide for the synthesis, maturation and release of hepatic LGP.

[Changes in lipoglycoprotein metabolism in toxic fatty liver].

COTTALASSO, DAMIANO;DOMENICOTTI, CINZIA MARIA;PRONZATO, MARIA ADELAIDE;NANNI, GIORGIO
1993

Abstract

A number of agents that produce liver injury also cause the accumulation of an abnormal amount of fat, predominantly triglycerides (TGs) in the parenchymal cells. Fatty liver (FL) is the result of an hepatocyte imbalance between the rate of synthesis and output of TGs into the plasma. TGs are not secreted as such, but combined with a glycoprotein moiety, and particularly with the very low density lipoproteins (VLDLs). This fraction is involved in the transport of hepatic TGs to extrahepatic tissues. FL can be induced by either acute or chronic administration of ethanol (EtOH), and/or several haloalkanes (carbon tetrachloride, CCl4; 1.2-dichloroethane, DCE; 1.1.2.2-tetrachloroethane, TTCE), both in laboratory animals and in man. Since the pathogenesis of this disease is a crucial problem, as yet undefined, the purpose of this article is to summarize the studies which have unraveled some of the mechanisms involved in FL, particularly the role played by impaired lipoglycoproteins (LGP) metabolism in rat liver.An important element in the pathogenesis of EtOH- and haloalkanes-induced FL is the impairment of hepatic secretion of VLDLs, which occurs soon after poisoning. Various steps of the secretory pathway are probably involved in the expression of such damage. The intoxication of rats with these xenobiotics leads to an early impairment of the hepatocyte system responsible for terminal glycosylation and maturation of LGP at the level of three different subfractions (F1, F2 and F3) of purified Golgi apparatus (GA). The earliest functional change is a block of LGP transit through the GA cisternae and vesicles, both in isolated hepatocyte model and in the whole animal. The glycosylation of LGP is a multistep process which starts in the rough endoplasmic reticulum (RER), and comes to its end in the GA. Dolichols (Dol) are a family of long-chain polyisoprenoid alcohols, present either as neutral free-Dol and dolichyl-phosphate (Dol-P). The latter acts as a glycosyl carrier across the RER membranes in the initial steps of LGP biosynthesis. Nearly all the other reactions occur in GA, where free-Dol have a role either in terminal LGP processing or in their secretion into the blood stream. Several investigations indicated that both EtOH and haloalkanes (CCl4, DCE, and TTCE) may selectively and precociously impair the total microsomes (TM) and GA pool of Dol, particularly in F1. Lipid peroxidation appears to be the fundamental mechanism involved.Such results, obtained in several works, point out a key role played in FL by selective impairment of MT and GA processes which provide for the synthesis, maturation and release of hepatic LGP.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/381203
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