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PubMed1987

alpha-Fetoprotein gene methylation and hepatocarcinogenesis in rats fed a choline-devoid diet.

We studied the alpha-fetoprotein (AFP) gene methylation of DNA from livers of rats fed choline-devoid or control choline-supplemented diets, and from hepatocellular carcinomas induced by the choline-devoid diet. Chronic choline deficiency caused a reduction in the level but not the pattern of methylation in hepatocytes. The tumors, however, had an altered methylation pattern with a marked increase in methylation at the 3' end, even those tumors that had low average DNA methylation. At the same time, there was a decrease in DNA methylation at the 5' end. The tumor methylation pattern resembled that of the active AFP gene of fetal liver but there was no increase in the steady-state level of AFP mRNA in the tumors. The 3' demethylated region is characteristic of the inactive adult liver AFP gene, but it disappears in the final stages of neoplastic transformation of hepatocytes. The methylation changes are not sufficient to activate the gene.

Animals↗
PubMed2026

Loss of Mtarc1 Protects Against Steatotic Liver Disease in Mice.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) spans from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and can progress to cirrhosis or hepatocellular carcinoma. Despite its prevalence, effective therapies are lacking. Recent genome-wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (MTARC1) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss-of-function MTARC1 variant, suggesting mARC1 inhibition as a potential MASLD treatment. METHODS: To validate mARC1 loss-of-function as protective against MASLD, we generated Mtarc1 knockout (KO) mice and placed them on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Effects of Mtarc1 KO on obesity and type 2 diabetes were explored using a high-fat diet. Hepatocytes from Mtarc1 KO mice were isolated to explore the molecular mechanisms by which Mtarc1 KO impacts lipid metabolism. RESULTS: Mtarc1 KO mice exhibited no vital growth or development defects. With a high-fat diet-induced obesity model, obese Mtarc1 KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD-induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in Mtarc1 KO mice. Primary hepatocytes isolated from Mtarc1 KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion. CONCLUSIONS: These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD/MASH.

Animals↗
PubMed2000

CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) and alcoholic liver disease have similar pathological features. Because CYP2E1 plays a key role in alcoholic liver disease with its ability to stimulate lipid peroxidation, we tested the proposal that CYP2E1 could also be a factor in the development of NASH. In a dietary model - mice fed a methionine- and choline-deficient (MCD) diet - liver injury was associated with both induction of CYP2E1 and a 100-fold increase in hepatic content of lipid peroxides. Microsomal NADPH-dependent lipid oxidases contributed to the formation of these lipid peroxides, and in vitro inhibition studies demonstrated that CYP2E1 was the major catalyst. To further define the role of CYP2E1 as an initiator of oxidative stress in NASH, Cyp2e1(-/-)mice were administered the MCD diet. CYP2E1 deficiency neither prevented the development of NASH nor abrogated the increased microsomal NADPH-dependent lipid peroxidation, indicating the operation of a non-CYP2E1 peroxidase pathway. In Cyp2e1(-/-) mice with NASH (but not in wild-type mice), CYP4A10 and CYP4A14 were upregulated. Furthermore, hepatic microsomal lipid peroxidation was substantially inhibited by anti-mouse CYP4A10 antibody in vitro. These results show that experimental NASH is strongly associated with hepatic microsomal lipid peroxidation. CYP2E1, the main enzyme associated with that process in wild-type mice, is not unique among P450 proteins in catalyzing peroxidation of endogenous lipids. We have now identified CYP4A enzymes as alternative initiators of oxidative stress in the liver.

Animals↗
PubMed1986

Light and electron microscopic studies of diet-induced hepatic changes in mice.

Adult mice were fed a choline-deficient ethionine enriched (CDE) diet for 24, 48 or 72 h. They were then fasted for 24 or 48 h prior to sacrifice. All tissues were studied by light and electron microscopy. Animals fed the CDE diet for 24 h exhibited cells with vacuolated cytoplasm, and the accumulation of lipid in these cells was clearly abnormal. Animals fed the CDE diet for 24 h and subsequently a regular diet for 48 h displayed normal hepatocytes, suggesting that the alterations at 24 h were reversible. Following 48 or 72 h of feeding the CDE diet, abundant lipid-laden cells were observed in the hepatic lobules, and at the electron microscope level these cells were undergoing frank degeneration. Evidence indicated that changes after 48 or 72 h were irreversible.

Animals↗
PubMedDate not supplied

Extracellular matrix remodeling may predominate over hepatocyte injury in hepatocellular carcinoma development.

It has been suggested that both extracellular matrix (ECM) remodeling and persistent hepatocyte injury play important roles in liver carcinogenesis process. It is, however, still controversial which factor plays a predominant role. The aim of the present study was to examine the role of each factor in the liver enzyme-altered preneoplastic lesions, focusing on the relationship between the hepatocyte injury and fibrosis extension. The effects of two similar herbal medicines (Sho-saiko-to and Saiko-keishi-to: TJ-9 and TJ-10, respectively) were elucidated on the hepatocyte injury, fibrosis and preneoplastic lesions development using a choline-deficient-L-amino acid-defined (CDAA) diet rat liver carcinogenesis model. TJ-9 prevented fibrosis and glutathione S-transferase placental form (GST-P)-positive preneoplastic lesion development without reducing the hepatocyte injury as indicated by the serum markers. TJ-10 significantly protected against the hepatocyte injury. However, it did not exert any inhibitory effect on fibrosis and the development of preneoplastic lesions. Our in vitro study revealed that TJ-9 markedly suppressed the hepatic stellate cell activation whereas TJ-10 did not. These results suggested that the ECM remodeling plays a more important role than the persistent hepatocyte injury in the liver enzyme-altered preneoplastic lesion development in the rat.

Amino Acids↗
PubMed2006

The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis.

Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are major phospholipids in mammalian membranes. In liver, PC is synthesized via the choline pathway or by methylation of PE via phosphatidylethanolamine N-methyltransferase (PEMT). Pemt(-/-) mice fed a choline-deficient (CD) diet develop rapid steatohepatitis leading to liver failure. Steatosis is observed in CD mice that lack both PEMT and multiple drug-resistant protein 2 (MDR2), required for PC secretion into bile. We demonstrate that liver failure in CD-Pemt(-/-) mice is due to loss of membrane integrity caused by a decreased PC/PE ratio. The CD-Mdr2(-/-)/Pemt(-/-) mice escape liver failure by maintaining a normal PC/PE ratio. Manipulation of PC/PE levels suggests that this ratio is a key regulator of cell membrane integrity and plays a role in the progression of steatosis into steatohepatitis. The results have clinical implications as patients with nonalcoholic steatohepatitis have a decreased ratio of PC to PE compared to control livers.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1986

Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.

The effects of the cholecystokinin (CCK)-receptor antagonist proglumide, the protease inhibitor gabexate, and the hormones secretin and cholecystokinin-octapeptide (CCK-8) were studied in a model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. Injections of gabexate and proglumide from initiation of CDE diet (before induction of pancreatitis) increased survival from 37% (diet alone) to 85 and 75%, respectively, and also ameliorated histological alterations and increases in serum amylase concentration and pancreatic activated trypsin. Secretin had no major beneficial effect. When proglumide or gabexate were given after induction of pancreatitis, proglumide still increased survival to 75%, whereas gabexate no longer did. Injection of nontoxic doses of CCK-8 before proglumide or gabexate injections completely abolished all beneficial effects and also increased the severity of pancreatitis due to CDE diet alone. Blockade of CCK receptors and early inhibition of protease activity may be beneficial in severe acute pancreatitis. Cholecystokinin appears to play a contributory role in the development of pancreatitis.

Acute Disease↗
PubMed2006

NADPH oxidase is not an essential mediator of oxidative stress or liver injury in murine MCD diet-induced steatohepatitis.

BACKGROUND/AIMS: Hepatic oxidative stress is a key feature of metabolic forms of steatohepatitis, but the sources of pro-oxidants are unclear. The NADPH oxidase complex is critical for ROS generation in inflammatory cells; loss of any one component (e.g., gp91phox) renders NADPH oxidase inactive. We tested whether activated inflammatory cells contribute to oxidant stress in steatohepatitis. METHODS: gp91phox-/- and wildtype (wt) mice were fed a methionine and choline-deficient (MCD) diet. Serum ALT, hepatic triglycerides, histopathology, lipid peroxidation, activation of NF-kappaB, expression of NF-kappaB-regulated genes and macrophage chemokines were measured. RESULTS: After 10 days of MCD dietary feeding, gp91phox-/- and wt mice displayed equivalent hepatocellular injury. After 8 weeks, there were fewer activated macrophages in livers of gp91phox-/- mice than controls, despite similar mRNA levels for MCP and MIP chemokines, but fibrosis was similar. NF-kappaB activation and increased expression of ICAM-1, TNF-alpha and COX-2 mRNA were evident in both genotypes, but in gp91phox-/- mice, expression of these genes was confined to hepatocytes. CONCLUSIONS: A functional NADPH oxidase complex does not contribute importantly to oxidative stress in this model and therefore is not obligatory for induction or perpetuation of dietary steatohepatitis.

Animals↗
PubMed1990

Protective action of luminal bile salts in necrotizing acute pancreatitis in mice.

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.

Acute Disease↗
PubMed1989

Bacterial infection is not necessary for lethal necrotizing pancreatitis in mice.

Sepsis is the most common cause of late death in pancreatitis. The presence of early bacterial infection has been correlated with the severity of the disease. A choline-deficient ethionine-supplemented (CDE) diet given to young female mice produces severe necrotizing pancreatitis that has morphologic and biochemical similarities to the human disease. We therefore searched for bacterial pancreatic infection in female CD-1 mice given the CDE diet. The mortality rate was 47.5% in mice fed the CDE diet. All of these mice had severe pancreatitis with inflammation, edema, and necrosis on histologic examination. Bacterial infection was present in 1/12 pancreatica among nonsurvivors and in 1/32 pancreatica in surviving animals (p not significant). Histologic examination showed edema to be more pronounced in surviving mice, although the overall severity of morphologic changes was not significantly different between survivors and nonsurvivors. We conclude that bacterial infection is not a determinant of the severity or lethality of experimental pancreatitis induced by the CDE diet.

Acute Disease↗
PubMed1983

Relationship between the functional status of the reticuloendothelial system and the outcome of experimentally induced pancreatitis in young mice.

Physiologically, the main function of alpha 2-macroglobulin is the binding of active endopeptidases rather than their inhibition. The interaction results in a conformational change in the alpha 2-macroglobulin that leads to its rapid elimination by the reticuloendothelial system. In this way, the reticuloendothelial system may help in the regulation of extracellular proteolytic activity resulting from the release of proteinases from injured pancreatic acinar cells in acute pancreatitis. To evaluate this concept, the effect of feeding a choline-deficient diet supplemented with 0.5% DL-ethionine was determined in 4 and 6-wk-old mice in which the reticuloendothelial system was normal, stimulated, or depressed. Stimulating the reticuloendothelial system in 4-wk-old mice significantly (a) decreased the mortality rate; (b) lessened the drop in the plasma content of both alpha 2-macroglobulin and alpha 1-antitrypsin; and (c) decreased the severity of pancreatitis noted microscopically. In contrast, reticuloendothelial suppression in this group of mice had no demonstrable effect. However, when similar studies were done in 6-wk-old mice, in which this diet induces a milder disease, reticuloendothelial suppression significantly increased the mortality rate as compared with normal mice, whereas reticuloendothelial stimulation significantly decreased it. The possible mechanism for the salutory effect of stimulating the reticuloendothelial system on the outcome of diet-induced pancreatitis in mice is discussed.

Age Factors↗
PubMed1997

An ETa/ETb endothelin antagonist ameliorates systemic inflammation in a murine model of acute hemorrhagic pancreatitis.

BACKGROUND: Endothelin peptides are polykines with strong vasoconstrictor properties. We have previously shown that endothelin antagonism (PD145065) reduces the local severity of acute pancreatitis. We now investigated the effect of endothelin antagonism on systemic inflammation in a model of acute hemorrhagic pancreatitis. METHODS: Forty-two mice were divided into four groups. Group 1 was fed standard food plus PD145065 every 8 hours. Group 2 was fed a choline-deficient ethionine (CDE) supplemented diet and given saline every 8 hours. Group 3 was fed a CDE diet and treated with PD145065 every 8 hours from initiation of diet. Group 4 was fed a CDE diet and given PD145065 from 48 hours after initiation of diet. Animals were killed at 70 hours. Serum was collected. Pancreata and lung tissue were harvested. RESULTS: Histology score, serum amylase level, lung myeloperoxidase, and interleukin (IL)-10 were all significantly reduced in both treatment groups (groups 3 and 4) (p < 0.05). IL-6 levels were reduced in group 3 only (p < 0.05). The mortality rate did not differ among any of the groups. CONCLUSIONS: Endothelin antagonism decreased the severity of acute pancreatitis and reduced markers of systemic inflammation. Late treatment at 48 hours failed to prevent the rise in IL-6. Mortality rates were unaffected by treatment.

Acute Disease↗
PubMed1985

Connection of ductlike structures induced by a chemical hepatocarcinogen to portal bile ducts in the rat liver detected by injection of bile ducts with a pigmented barium gelatin medium.

Newly found metaplastic ductlike structures that form in the liver of rats exposed to carcinogens are connected to preexisting bile ducts. Male Fischer rats fed a diet of N-2-acetylaminofluorene in a choline-deficient diet (CDAAF) develop a massive proliferation of oval cells which appear to differentiate into bile-ductlike structures. However, unlike normal or proliferating bile ducts, these ductlike structures contain alpha-fetoprotein (AFP) and albumin, which are markers for proliferating hepatocytes and some hepatocellular carcinomas. Bile duct injections with a green pigmented barium gelatin medium filled the lumens of the ductlike structures and typical ductlike structures induced by the CDAAF diet, as well as the proliferating bile ducts induced by the noncarcinogenic alpha-naphthylisothiocyanate (ANIT), and the ducts in the normal controls. AFP was present in the ductlike structures in the rats fed AAF, but not in the bile ducts of animals fed ANIT. These studies suggest that most, if not all, of the ductlike structures produced during chemical hepatocarcinogenesis are derived from bile ducts, yet have the capacity to produce AFP and albumin.

2-Acetylaminofluorene↗
PubMed2005

Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury.

The liver regenerates after acute injury via hepatocyte cell division; during chronic injury, when hepatocyte replication is impaired or blocked, liver progenitor oval cells mediate liver regeneration. If both regeneration options are blocked in animal models, then liver failure and death ensues. The mechanisms underlying oval cell induction, proliferation, and subsequent liver regeneration remain poorly characterized. In particular, cell-signaling pathways that distinguish the alternative pathways are unknown. This study shows that in a mouse model, hepatic expression of lymphotoxin-beta (LTbeta) and interferon gamma (IFNgamma) transcripts is increased in response to the choline-deficient, ethionine-supplemented (CDE) diet, which induces oval cell-mediated liver regeneration. Oval cells express LTbeta and IFNgamma transcripts, contributing to the increased expression in the liver of mice fed the CDE diet. An attenuated oval cell response to such a diet was observed in LTbeta receptor-, LTbeta-, and IFNgamma-gene targeted mice. Loss of LTbeta and LTbeta receptor signaling reduced the number of oval cells expressing A6 and muscle pyruvate kinase. The lack of IFNgamma signaling reduced muscle pyruvate kinase(+), but not A6(+), oval cells. In contrast, partial hepatectomy suppressed LTbeta and IFNgamma transcripts. We also show that IFNgamma induces STAT-3 phosphorylation in an oval cell line. In conclusion, LTbeta, LTbeta receptor, and IFNgamma are involved in oval cell-mediated, but not hepatocyte-mediated, liver regeneration, and the absence of these pathways impairs the oval cell-dependent regenerative response.

Acute Disease↗
PubMed1989

Alpha 1-antitrypsin levels predict mortality from ethionine-induced pancreatitis in mice.

Experimental pancreatitis can be induced by an ethionine-containing, choline-deficient diet in mice. We investigated the role of circulating alpha 1-antitrypsin in this model using two strains of mice: ICR and C57BL-6. A 50% reduction in circulating alpha 1-antitrypsin occurred in all mice by day three of diet exposure. Total protein was reduced by only 9% and albumin was unchanged. Female mice of both strains had significantly lower alpha 1-antitrypsin levels than male mice prior to and after diet exposure. This was associated with significantly greater mortality in both female strains. Interstrain comparisons showed a significantly higher mortality in the C57BL-6 females (100%) compared to the ICR females (58%); this corresponded to significantly lower alpha 1-antitrypsin levels in C57BL-6 females. Regardless of sex or strain, alpha 1-antitrypsin levels prior to and after diet exposure were significantly higher in mice surviving than in mice dying. We conclude that circulating alpha 1-antitrypsin is a predictor of mortality from diet-induced pancreatitis.

Animals↗
PubMed2002

KF24345, an adenosine uptake inhibitor, ameliorates the severity and mortality of lethal acute pancreatitis via endogenous adenosine in mice.

Adenosine protects against cellular damage and dysfunction under several adverse conditions including inflammation and ischemia. In this study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on experimental acute pancreatitis induced by choline-deficient and ethionine-supplemented diet in mice. KF24345, administered with the diet onset and every 24 h thereafter, prevented hyperamylasemia, acinar cell injury and serum tumor necrosis factor-alpha elevation and ultimately decreased mortality. Therapeutic treatment with KF24345, which started 32 h after the diet onset, also decreased mortality. The beneficial effect of KF24345 on mortality was abolished by the pretreatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), a selective adenosine A(2A) receptor antagonist. An intravenous injection of KF24345 at 48 h after the diet onset increased plasma adenosine concentrations in mice with acute pancreatitis. These results suggest that KF24345 shows anti-pancreatitis effects via endogenous adenosine and adenosine A(2A) receptors. The adenosine uptake inhibition could be a new therapeutic approach for acute pancreatitis.

Acute Disease↗
PubMed2000

Differentiation status of rat ductal cells and ethionine-induced hepatic carcinomas defined with surface-reactive monoclonal antibodies.

To gain further insight into the differentiation of oval cells and their role in carcinogenesis, we have generated cell surface reactive monoclonal antibodies (MAbs) by a Balb/c nude mouse (nu/nu) immunization protocol. Three MAbs designated OC.4, OC.5, and OC.10 were generated from a mouse immunized with CDE6, an oval cell line established from oval cells induced by feeding a choline-deficient diet containing 0.1% ethionine (CDE). These MAbs demonstrated stage-specific expression in fetal liver and displayed strong reactivity with oval and bile duct epithelial cells. In general, oval cells displayed a more mature phenotype than fetal ductal cells, suggesting the existence in adult liver of more primitive ductal progenitors. A fourth MAb recognized a cytoplasmic antigen (OC.6) expressed by mucus-secreting hepatic ducts induced by CDE diet. Immunocytochemical analysis indicated that OC.4, OC.5, and OC.10 were also expressed on CDE-induced, OV6+ hepatocellular carcinomas (HCC) but not on OV6+ HCC induced by the Solt/Farber protocol. In most cases, CDE-induced, OV6+ HCC expressed early ductal developmental markers such as OC.10 but lacked those expressed at later stages (OC.5, OC.4). These new MAb will be useful for characterizing HCC subpopulations with oval cell characteristics and for isolating biliary cells at antigenically defined stages during differentiation.

Animals↗
PubMedDate not supplied

Inhibitory effect of ursodeoxycholic acid on the progression of chronic hepatic disorders with special reference to increases in blood flow.

Ursodeoxycholic acid (UDCA), which is commonly used as a cholesterol-gallstone-dissolving agent, is now expected to be effective not only for primary biliary cirrhosis but for chronic active hepatitis as well. In this study, we administered 0.1% ethionine-added, choline-deficient diet for 8 weeks to male Sprague-Dawley rats to prepare an animal model of chronic hepatic disorders. At the same time, UDCA (50 mg/kg/day) was administered orally to these animals, and its effects on the liver, including effects on hepatic blood flow determined with a laser Doppler blood flow meter, were evaluated. Hepatic blood flow increased significantly in the UDCA group compared with the untreated groups. Transaminase levels decreased significantly in the UDCA group compared with the untreated group. Histologic differences were noted between the UDCA and untreated groups in histopathologic examinations of the liver, with liver cirrhosis or early liver cirrhosis being present in the untreated group, compared with only chronic active hepatitis in the UDCA group. These findings suggest that UDCA is able to prevent or inhibit the progression of chronic hepatic disorders, an effect that may be due in part to increases in hepatic blood flow.

Alanine Transaminase↗