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Abnormal lipid composition of microsomes from cirrhotic rat liver--does it contribute to decreased microsomal
J Reichen1, J T Buters, Z Sojcic
1Department of Clinical Pharmacology, University of Bern, Switzerland.
Abstract:
We determined to what extent a change in the lipid composition of the smooth endoplasmic reticulum contributes to altered microsomal function in cirrhosis. Rats were rendered cirrhotic either by chronic exposure to phenobarbital/CCl4 (MCIR) or by bile duct ligation (BCIR). Microsomal function was tested in vivo by the aminopyrine breath test (ABT), then microsomes were prepared and their phospholipid and cholesterol composition analysed. ABT was reduced by 35 and 41% in BCIR and MCIR, respectively. Cholesterol in microsomes was increased in both cirrhotic groups. (BCIR + 154%, MCIR + 75%) while total phospholipid content was not affected. As shown in other membrane systems, the phospholipid/cholesterol (PL/XOL) ratio showed an excellent inverse correlation with fluorescence anisotropy determined by diphenylhexatriene fluorescence polarization (r = -0.896). The PL/XOL ratio was significantly correlated with aminopyrine N-demethylation in vivo (r = 0.649). Alterations in the composition of phospholipid groups (an increase in sphingomyelin in both cirrhotic groups, and a decrease in phosphatidylcholine and an increase in phosphatidylethanolamine in BCIR) also contributed to increased membrane rigidity. We conclude that altered membrane fluidity contributes to diminished microsomal function but that other factors must also be involved since the PL/XOL ratio explained only 42% of the variance in aminopyrine N-demethylation.
Insights
Cirrhosis alters liver cell membranes, increasing cholesterol and rigidity. This impacts microsomal function, crucial for drug metabolism, but doesn't fully explain the decline.
Area of Science:
- Hepatology
- Biochemistry
- Cell Biology
Background:
- Cirrhosis significantly impacts liver function.
- Microsomal function is vital for drug metabolism and detoxification.
- Changes in the smooth endoplasmic reticulum's lipid composition are implicated in disease.
Purpose of the Study:
- To investigate the role of lipid composition changes in the smooth endoplasmic reticulum of cirrhotic rat livers.
- To correlate these changes with altered microsomal function.
Main Methods:
- Induction of cirrhosis in rats using phenobarbital/CCl4 (MCIR) or bile duct ligation (BCIR).
- Assessment of in vivo microsomal function using the aminopyrine breath test (ABT).
- Analysis of microsomal phospholipid and cholesterol composition and membrane fluidity (fluorescence polarization).
Main Results:
- Both MCIR and BCIR models showed reduced ABT results, indicating impaired microsomal function.
- Cirrhotic microsomes exhibited significantly increased cholesterol content.
- The phospholipid/cholesterol ratio inversely correlated with membrane rigidity and positively with N-demethylation, but only explained 42% of functional variance.
Conclusions:
- Altered lipid composition, particularly increased cholesterol, contributes to increased membrane rigidity and diminished microsomal function in cirrhosis.
- While membrane fluidity is a key factor, other mechanisms also contribute to the observed functional deficits in cirrhotic livers.