The state of cholesterol metabolism in the liver of patients with primary biliary cirrhosis: the role of MDR3 expression

Abstract

Aim Because dyslipidemia, such as hypercholesterolemia, is a characteristic of primary biliary cirrhosis (PBC), hepatic lipid metabolism may be disturbed in PBC patients. We examined the expression of lipid metabolism-associated genes in PBC liver. Methods All of the patients examined were in stage I or II PBC and without medication. RNA was isolated from liver specimens by needle biopsies of PBC patients and controls. The expression levels of various genes were measured by real-time RT-PCR. Multidrug resistance 3 (MDR3) expression was examined immunohistochemically. Statistical correlations between the gene expression levels and indices of blood testing were calculated. Results The expression levels of sterol regulatory element-binding protein (SREBP) 2 and LDL receptor were significantly lower, and those of apolipoprotein B, microsomal triglyceride transfer protein, ATP-binding cassette G5, and liver X receptor a (LXRa) were significantly higher in the PBC liver than in the normal control liver. The expression levels of bile acid synthesis-and excretionassociated genes did not change, and those of farnesoid X receptor, peroxisome proliferator-activated receptor a, and SREBP-1c were similar between the PBC and normal liver. MDR3 gene expression levels in the PBC liver were more than 4-fold higher than those in the control liver. Immunohistochemically, strong canalicular staining for MDR3 was observed in the PBC liver. LXRa expression was positively correlated with MDR3 levels. Serum levels of c-glutamyl transpeptidase (GGT) and IgM were negatively correlated with MDR3 levels. Conclusions Hepatocellular cholesterol metabolism was at least partially disturbed, even in the early stage of PBC. The most characteristic finding was a distinct elevation of MDR3 expression, and the MDR3 levels were negatively correlated with GGT and IgM levels.

Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid

“…However, MDR3 is activated by both bezafibrate as well as UDCA 7. Furthermore, recent reports have demonstrated that the expression of MDR3 was already markedly up‐regulated in PBC patients30 and it was not significantly affected by bezafibrate treatment 31. Therefore, the anticholestatic effect of bezafibrate may be caused by mechanisms independent of phospholipid secretion.…”

Lipid Metabolism and the Liver

“…Primary biliary cholangitis (PBC) represents a physiological response of the liver to intracellular cholesterol accumulation; specifically, cholesterol uptake and synthesis are suppressed, while secretion and excretion are enhanced [66]. The transcription levels of SREBP2, LDLR, HMGR, and NPC1L1, all of which are associated with cholesterol uptake and synthesis, were found to be downregulated.…”

Hepatobiliary anomalies associated with ABCB4/MDR3 deficiency in adults: a pictorial essay

“…The ‘unchaperoned’ bile acids in the bile of patients with MDR3 deficiency may cause chronic cholangitis. Several other biliary disorders have been associated with ABCB4 /MDR3 mutations: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP), drug-induced liver injury, transient neonatal cholestasis [TNC], adult biliary fibrosis or cirrhosis [3], and very recently intrahepatic cholangiocarcinoma (IHCC) [4–9]. …”