Biomedical subjects

S H Zeisel

Publications and source records attributed to S H Zeisel.

At least 19 recordsLinked to original sources

PubMed1996

Choline deficiency induces apoptosis in SV40-immortalized CWSV-1 rat hepatocytes in culture.

Immortalized CWSV-1 rat hepatocytes, in which p53 protein is inactivated by SV40 large T antigen, had increased numbers of cells with strand breaks in genomic DNA (terminal dUTP end labeling) when grown in 0 Micron choline (67-73% of cells) than when grown in 70 Micron choline (2-3% of cells). Internucleosomal fragmentation of DNA (DNA ladders) was detected in cells grown with 5 Micron and 0 Micron choline for 72h. Cells treated with 0 or 5 Micron choline for 72h detached from the substrate in high numbers (58% of choline deficient cells vs. 1.4% of choline sufficient cells detached) exhibited a high incidence of apoptosis (apoptotic bodies were seen in 55-75% of cells; 67-73% had DNA strand breaks), and an absence of mitosis and proliferating cell nuclear antigen (PCNA) expression. Cells undergoing DNA fragmentation had functioning mitochondria. At 24h, cells grown in 0 or 5 Micron choline synthesize DNA more rapidly than those grown in 70 Micron choline. By 72h, the cells grown in 0 or 5 Micron choline were forming DNA much more slowly than control cells (assessed by thymidine incorporation, PCNA expression, and mitotic index). Western blot analysis showed that p53 in the nucleus of cells was detected in direct association with SV40 T-antigen, and was therefore likely to be inactive. We conclude that choline deficiency kills CWSV-1 hepatocytes in culture by inducing apoptosis via what may be a p53-independent process, and that this process begins in viable cells before they detach from the culture dish.

Animals↗

PubMed1995

Nutrients, signal transduction and carcinogenesis.

Choline phospholipids play major roles in cellular regulation in addition to their essential function as structural components of membranes and lipoproteins. The unique functions of choline phospholipids as hormones (platelet activating factor, 1-alkyl, 2-acetylphosphatidylcholine, PAF) and sources (phosphatidylcholine, sphingolipids) of second messengers (sphingosine, diacylglycerol, lysophospholipids, arachidonic acid and its metabolites) may explain how dietary choline influences normal physiological processes as well as a diverse group of pathological processes, including carcinogenesis.

Animals↗

PubMed1995

Choline and hepatocarcinogenesis in the rat.

Rats fed a choline deficient diet develop foci of enzyme-altered hepatocytes with subsequent formation of hepatic tumors. This is the only nutritional deficiency that, in itself, causes cancer. We suggested that carcinogenesis is triggered, in part, because of abnormalities in cell signals which regulate cell proliferation and cell death. Because choline deficient rats develop fatty liver (choline is needed for hepatic secretion of certain lipoproteins), we examined whether an important lipid second messenger involved in proliferative signaling, 1,2-sn-diacylglycerol, accumulated in liver and resulted in the prolonged activation of protein kinase C. We observed that 1,2-sn-diacylglycerol accumulated in the plasma membrane from the non-tumor portion of livers of rats fed a choline deficient diet, and that unsaturated free fatty acids, another activator of protein kinase C, also accumulated in deficient livers. Protein kinase C in the hepatic plasma membrane and nucleus of choline deficient rats was elevated for months; this is the only model system which exhibits such prolonged activation of protein kinase C. Premalignant, abnormal hepatic foci were detected only in the deficient rats, and 15% of deficient rats (none of the controls) had hepatocellular carcinoma at 1 year on the diet. In rats, an early event in choline deficiency is an increase in the rate of cell death. In liver from choline deficient rats, we observed an increase in the numbers of liver cells with fragmented DNA (characteristic of programmed cell death; apoptosis). We used a cell culture model (immortalized rat hepatocytes) to study the effects of choline deficiency on apoptosis. Liver cells grown in a choline deficient medium became depleted of choline, accumulated triacylglycerol and 1,2-sn-diacylglycerol, and had increased DNA fragmentation and other morphologic and biochemical changes associated with apoptosis. This model has great potential as a tool for studying the underlying link between choline deficiency and the regulation of the balance between cell proliferation and cell death. We suggest that choline deficiency altered the cell proliferation signals mediated by protein kinase C within liver, and altered cell apoptosis. These changes in cell signaling may be the triggering events which result in hepatic carcinogenesis.

Animals↗

PubMed1995

Radioactive choline metabolism in guinea pig gallbladder. Is there measurable acetylcholine release?

Acetylcholine may be released from gallbladder intrinsic nerves in response to cholecystokinin stimulation. This study characterized metabolites of [14C]choline produced in the gallbladder and released during incubation, with or without cholecystokinin-octapeptide. Radiolabeled [14C]choline was applied to the mucosal or muscle surface of intact guinea pig gallbladders in an organ bath. After radiolabeling, gallbladders were incubated with or without the contractile agonist cholecystokinin-octapeptide. Metabolites of [14C]choline were identified in gallbladder tissue and incubation buffers using HPLC and thin-layer chromatography. The major metabolites of [14C]choline were betaine and phosphocholine. [14C]Phosphocholine was incorporated slowly into [14C]phosphatidylcholine. [14C]Choline was released into buffers during incubation. [14C]Acetylcholine constituted less than 1% of radiolabel in the gallbladder. There was no identifiable [14C]acetylcholine released in buffers. Cholecystokinin-octapeptide did not affect choline metabolism. These studies showed that choline in the gallbladder is metabolized along pathways similar to those in the liver. Gallbladders released mostly choline, rather than acetylcholine, even during hormonally induced contraction.

Acetylcholine↗

PubMed1995

Effects of prolonged (1 year) choline deficiency and subsequent re-feeding of choline on 1,2-sn-diradylglycerol, fatty acids and protein kinase C in rat liver.

Rats fed a choline-deficient diet develop foci of enzyme-altered hepatocytes with subsequent formation of hepatic tumors. They also develop fatty livers, because choline is needed for hepatic secretion of lipoproteins. We have previously reported that 1,2-sn-diradylglycerol accumulates in the livers of rats fed a choline-deficient diet for 1-27 weeks, and that protein kinase C activity in the hepatic plasma membrane is elevated during that time (da Costa et al., J. Biol. Chem., 268, 2100-2105, 1993). In the present study, we examined the changes that occur in rat liver at 52 weeks of choline deficiency and determined whether these changes were reversible when choline was returned to the diet of the deficient animals for 1 or 16 weeks. At 52 weeks, non-tumor liver samples from the experimental animals had increased 1,2-sn-diradylglycerol concentrations in the lipid droplets compared with control animals. Plasma membrane 1,2-sn-diradylglycerol levels in the liver did not differ between the two groups, but an age-related increase in membrane 1,2-sn-diradylglycerol concentrations was observed. Unsaturated free fatty acids, another activator of protein kinase C, accumulated in the deficient livers. Protein kinase C activity associated with the plasma membrane remained significantly elevated at 52 weeks in deficient livers. Hepatic foci expressing gamma-glutamyltranspeptidase were detected only in the deficient rats (0.83% of liver volume) and 15% of these rats had hepatocellular carcinoma at 1 year on the diet. At 53 weeks (1 week after choline was returned to the deficient group), 1,2-sn-diradylglycerol concentrations in the lipid droplets and hepatic free fatty acids had dropped to control levels. By 68 weeks (16 weeks of re-feeding choline), the membrane protein kinase C activity had returned to normal. At this time, 14% of the experimental animals had hepatocellular carcinoma. We suggest that choline deficiency altered the protein kinase C-mediated signal transduction within liver and this contributed to hepatic carcinogenesis in these animals.

Aging↗

PubMed1995

Choline distribution and metabolism in pregnant rats and fetuses are influenced by the choline content of the maternal diet.

Choline supplementation of pregnant rats between d 12 and 17 of pregnancy permanently enhances the spatial memory of offspring; however, the mechanism is unknown. We examined the effect of choline supplementation on metabolism of orally ingested choline by nonmated rats and pregnant rats and their fetuses. We studied the metabolism of an acute oral dose of 14C-choline chloride in pregnant and nonmated rats with and without choline supplementation (25 mmol/L choline chloride in water) on d 12-17 of pregnancy. During the first 2 h after oral dosing, plasma radiolabeled choline was detectable, whereas plasma choline metabolites contributed little to total radioactivity at any time. The pattern of accumulation of label in placentas was similar in all groups. Fetal tissues (i.e., brain, liver and carcass remnant) contained primarily 14C-phosphatidylcholine and 14C-phosphorylcholine. Also, we examined the fetal tissue distribution of isotopically labeled (deuterated) choline derived from the diet and from the dietary choline supplement. The distribution patterns for radiolabeled choline metabolites in fetuses of supplemented dams accumulated significantly (P < 0.01) more of their total choline and its metabolites than fetuses of control dams during d 12-17 of gestation (50 vs. 20%). In fetuses from supplemented dams, betaine concentrations were greater than in fetuses from control dams in all organs assayed (by 36-57%). Phosphorylcholine concentrations in brain of fetuses from supplemented dams were also greater. These experiments identify potential metabolites of choline that might mediate the observed effects on brain development in the rats.

Administration, Oral↗

PubMed1995

Pregnancy and lactation are associated with diminished concentrations of choline and its metabolites in rat liver.

Choline is an important nutrient that is actively transported from mother to fetus across the placenta and from mother to infant across the mammary gland. Thus, pregnancy and lactation are times when dietary requirements for choline may be increased. Pregnant rats eating AIN-76A diet (with and without choline) for 6 d (d 12-18 gestation) were compared with nonmated female and male rats eating the same diets. Similarly, lactating rats were compared with nonmated female rats, both groups eating these same diets for 25 d (gestation d 12-postpartum d 15). We measured choline and choline metabolites in livers on the last day of feeding. Nonmated female rats, eating the control diet, had higher hepatic choline metabolites concentrations than did male rats (choline, 98%; betaine, 96%; and phosphorylcholine, 55% higher), pregnant rats (phosphorylcholine, 47%; and betaine, 42% higher) or lactating rats (phosphorylcholine, 49%; phosphatidylcholine, 37%; and betaine, 273% higher). We found that nonmated females eating a choline deficient diet had only a modest diminution (33%) of the labile choline metabolite PCho in liver, compared with similar rats eating a control diet. When compared with similar rats fed a choline-adequate diet, pregnant rats fed a choline-deficient diet had significantly great diminution of hepatic phosphorylcholine (83% lower) than did nonmated females. Liver phosphorylcholine was only 12% lower than in controls in nonmated females fed the deficient diet for the same 25-d period. Lactating rats were the most sensitive to choline deficiency, with liver phosphorylcholine 88% lower than in similar rats fed control diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver.

It has previously been shown that choline deficiency causes depletion of hepatic folate concentration in rats. Two separate experiments were undertaken to investigate the converse phenomenon: whether folate deficiency would lead to depletion of hepatic choline. In Experiment 1, severe folate deficiency was induced in rats by feeding an amino acid-defined diet containing (per kg diet) 1.4 g choline, 0 mg folate and 10 g succinylsulfathiazole. Control rats were fed the same diet containing 8 mg folate/kg. After 4 wk, plasma and hepatic folate concentrations were significantly depleted in the severely folate-deficient rats compared with controls (P < 0.001), and hepatic choline and phosphocholine concentrations were 65 and 80% lower, respectively (P < 0.001). In Experiment 2, moderate folate deficiency was induced in rats by feeding the same diet as described above, but with the succinylsulfathiazole omitted. After 24 wk, significant systemic folate deficiency was present in the moderately folate-deficient rats compared with controls (P < 0.001). A modest reduction (36%, P = 0.087) in hepatic choline concentration was observed in the moderately folate-deficient rats compared with controls. No significant differences in hepatic phosphocholine concentrations were detected between the two groups. These results indicate that severe folate deficiency causes secondary hepatic choline deficiency in rats.

Animals↗

PubMed1994

Lecithin and choline in human health and disease.

Choline is involved in methyl group metabolism and lipid transport and is a component of a number of important biological compounds including the membrane phospholipids lecithin, sphingomyelin, and plasmalogen; the neurotransmitter acetylcholine; and platelet activating factor. Although a required nutrient for several animal species, choline is not currently designated as essential for humans. However, recent clinical studies show it to be essential for normal liver function. Additionally, a large body of evidence from the fields of molecular and cell biology shows that certain phospholipids play a critical role in generating second messengers for cell membrane signal transduction. This process involves a cascade of reactions that translate an external cell stimulus such as a hormone or growth factor into a change in cell transport, metabolism, growth, function, or gene expression. Disruptions in phospholipid metabolism can interfere with this process and may underlie certain disease states such as cancer and Alzheimer's disease. These recent findings may be appropriate in the consideration of choline as an essential nutrient for humans.

Animals↗

PubMed1994

Choline and human nutrition.

Choline is crucial for sustaining life. It modulates the basic signaling processes within cells, is a structural element in membranes, and is vital during critical periods in brain development. Choline metabolism is closely interrelated with the metabolism of methionine and folate. We believe that the normal human diet provides sufficient choline to sustain healthy organ function. However, vulnerable populations may become choline deficient, including the growing infant, the pregnant or lactating woman, the cirrhotic, and the patient fed intravenously. Further studies of choline requirements in these groups are required.

Animals↗

PubMed1993

Characterization of choline metabolism and secretion by human placental trophoblasts in culture.

Choline is an essential nutrient for fetal development and may be utilized to form phospholipids such as phosphatidylcholine and sphingomyelin; to synthesize the neurotransmitter, acetylcholine; and to donate methyl groups after being oxidized to betaine. Since the majority of choline required for fetal growth must be transported by the placenta from the maternal circulation, we examined the ability of isolated human trophoblasts to metabolize choline and to release choline and its metabolites into culture medium. Cytotrophoblasts were isolated from normal, full-term human placentas and incubated with [14C]choline for 3 h; the cells were washed to remove extracellular radiolabel, and the changes in intracellular and medium choline pools were followed for an additional 24 h. During the incubation, choline rapidly reached steady state intracellularly and label was incorporated into betaine, phosphocholine, cytidylyldiphosphocholine, phosphatidylcholine, glycerophosphocholine, lysophosphatidylcholine, and sphingomyelin. All labeled choline metabolites in cells, except glycerophosphocholine, decreased at 6 and 27 h of incubation (3 and 24 h, respectively, after labeled choline was removed), and labeled metabolites appeared in media. By 24 h after labeled choline was removed, the major labeled metabolites in the media were choline (82%), betaine (11%), and glycerophosphocholine (5%). Small amounts of phosphatidylcholine (1%), and lysophosphatidylcholine (1%) were found. Acetylcholine was a very minor choline metabolite in these cells. When placental cells were incubated for 66 h after isolation, they formed syncytiotrophoblasts, which incorporated labeled choline into metabolites in a similar pattern to cytotrophoblasts. These data indicate that isolated trophoblast cells can metabolize choline to form all of its major metabolites and that several metabolites are released to the medium in significant amounts. Thus, our data suggest that the major metabolite supplied to the fetus may be choline, but that betaine and glycerophosphocholine may also be vehicles for transfer of choline equivalents from mother to fetus.

Betaine↗

PubMed1993

Choline phospholipids: signal transduction and carcinogenesis.

Phospholipids act as vital elements in transmembrane signaling. Agonist-induced hydrolysis of phosphatidylinositides has been established as a major mechanism for transmitting messages into the interior of cells via protein phosphorylation cascades, ultimately regulating gene transcription. There is a growing body of evidence that choline phospholipids (phosphatidylcholine, sphingomyelin, and their metabolites) also are important mediators and modulators of transmembrane signaling. These functions may explain how choline phospholipids influence normal physiological processes as well as a diverse group of pathological processes.

Animals↗

PubMed1993

Accumulation of 1,2-sn-diradylglycerol with increased membrane-associated protein kinase C may be the mechanism for spontaneous hepatocarcinogenesis in choline-deficient rats.

Choline deficiency, via deprivation of labile methyl groups, is associated with a greatly increased incidence of hepatocarcinoma in experimental animals. This dietary deficiency also causes fatty liver, because choline is needed for hepatic secretion of lipoproteins. We hypothesized that fatty liver might be associated with the accumulation of 1,2-sn-diradylglycerol and subsequent activation of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction. We observed that rats fed a choline-deficient diet for 1, 6, or 27 weeks had increased hepatic concentrations of 1,2-diradylglycerol. At 1 and 6 weeks, hepatic plasma membrane from choline-deficient rats had increased concentrations of 1,2-sn-diacylglycerol and 1-alkyl, 2-acylglycerol, with the latter accounting for 20-26% of membrane 1,2-sn-diradylglycerol (as compared with only 2-5% in controls). Protein kinase C activity was increased in hepatic plasma membrane at 1 week of choline deficiency. By Western blotting there was an increase in the amount of protein kinase C zeta and a decrease in the amount of protein kinase C delta in liver at 1 week. By 6 weeks of choline deficiency, hepatic plasma membrane and cytosolic protein kinase C (PKC) activities were increased significantly, with increased amounts of hepatic plasma membrane protein kinase C alpha, and delta detected by Western blotting. Glycogen synthase activity in liver was diminished after 1 week of choline deficiency; this enzyme is inhibited by PKC-mediated phosphorylation. We suggest that choline deficiency perturbed PKC-mediated transmembrane signaling within liver and that this contributed to the development of hepatic cancer in these animals.

Animals↗

PubMed1993

Lipid synthesis and secretion by primary cultures of rat mammary epithelial cells.

Lipid synthesis and secretion was measured in primary rat mammary epithelial cells cultured on basement matrix in medium supplemented with lactogenic hormones. The cells grew and differentiated to form alveolar-like structures reminiscent of lactating mammary gland. They synthesized abundant triacylglycerol, containing fatty acids characteristic of rat milk (C10:0-C14:0), using 14C-glucose, 14C-oleic acid or 14C-glycerol as precursors. Basal levels of triacylglycerol secretion were measured using 14C-oleic acid labeling; 1.3 +/- 0.3% of the labeled cellular triacylglycerol was secreted into the medium in 24 hours. Secreted lipid droplets were surrounded by a bilayer membrane with an electron-dense inner coat characteristic of fat globules secreted by the mammary gland. The rate of triglycerol secretion was increased to 998 +/- 98% of control (P < 0.01) by the addition of phorbol 12-myristate 13-acetate (PMA) in combination with staurosporine, a protein kinase inhibitor. Several other protein kinase inhibitors, when combined with PMA, also markedly stimulated secretion. Effective protein kinase inhibitors included sphingosine (has diverse cellular effects including the inhibition of protein kinase C; 13-fold increase in secretion), and KT5823 (a cGMP dependent protein kinase inhibitor; 5-fold increase). KT5720 (a cAMP-dependent protein kinase inhibitor) did not alter secretion. Kinase inhibitors were effective only in the presence of a phorbol ester. 4 alpha-phorbol-12,13-didecanoate, a phorbol ester which does not activate protein kinase C (PKC), could substitute for PMA. Lipid release was not mediated by disruption of cell-cell tight junctions, as EGTA did not release lipid. Based on these observations we suggest that two signals are needed to enable or stimulate lipid secretion in cultured rat mammary epithelial cells: 1) inhibition of a protein kinase and 2) a PKC-independent effect of phorbol ester. We have, for the first time, characterized a cell culture model suitable for studying lipid synthesis and secretion by mammary epithelial cells.

Animals↗

PubMed1993

Diet and carcinogenesis.

In summary there is a wealth of information on dietary and nutritional effects on carcinogenesis in laboratory rodents. Experimental studies based on epidemiological evidence, earlier experimental studies and known or predicted cellular, biochemical and molecular effects of nutrients have produced clear evidence that carcinogenesis in laboratory rodents is influenced by dietary intake of calories, fat, lipotropes (choline, methionine), vitamin A and related retinoids, Se, calcium, zinc, fiber, ethanol and a large number of non-nutrient components of foods. For these substances or groups of substances mechanistic hypotheses supported by experimental data and are leading to further research. The information provided will contribute to understanding of basic processes in carcinogenesis as well as of the specific interactions studied, and should contribute to significant advances in preventive medicine. Restriction of caloric intake of rodents by amounts > 10% over a significant portion of their lifetime reduces tumorigenesis. That level of restriction reduces the rate of growth and maturation, and most experiments in this area employ greater restrictions that virtually abolish growth from a young age. Therefore, the observations are of interest in mechanistic studies, but their applicability to preventive medicine requires better definition of the degree and duration of restriction required for a significant effect and the age at which it must be imposed. Restriction of total fat intake and modifications to increase the intake of omega-3 fats have a reasonably consistent effect on tumorigenesis in rodents but a much less consistently demonstrable effect in humans. Again, the observations in rodents are providing a major stimulus to mechanistic studies. The lipotropes are extremely valuable as tools for investigating mechanisms of carcinogenesis in rodents. Their importance in the epidemiology of human cancer has yet to be demonstrated clearly and is a subject of research at present. The naturally occurring vitamins and minerals, as well as fiber, derive their importance in this context from investigations to explain the consistent epidemiological demonstrations of reduction of tumor risk with increased consumption of fruits and vegetables. The activity of the isolated nutrients as anticarcinogens in rodents has generally not matched the activity expected from epidemiological studies. The anticarcinogenic activity of many of the non-nutrient components of fruits and vegetables is remarkable in particular models, however, as is the activity of natural and synthetic retinoids. At present the results must be interpreted to indicate an important effect of combinations of the whole foods with identification of particular nutrients or non-nutrients in specific cases.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Drinking↗

PubMed1993

Glycerophosphocholine and phosphocholine are the major choline metabolites in rat milk.

Choline is a constituent of cell membranes, surfactant and acetylcholine and is also a major source of methyl groups for the regeneration of methionine from homocysteine. Previous analyses of rat, human and bovine milk measured only choline, phosphatidylcholine and sphingomyelin. Choline-containing compounds in milk from rats lactating for 15 d were measured by HPLC and gas chromatograph-mass spectrometry. In addition to the previously reported choline metabolites, substantial concentrations of glycerophosphocholine (3.7 mmol/L) and phosphocholine (653 mumol/L) were also detected. At 1 h after oral administration of [methyl-14C]choline to lactating rats, the major labeled metabolites were phosphocholine (91% of label in milk) and betaine (9%). Twenty-four hours after the dose, glycerophosphocholine was the major labeled metabolite (69% of label in milk). Rat mammary epithelial cells, in primary culture, synthesized and secreted phosphatidylcholine, phosphocholine, glycerophosphocholine and betaine. Thus, the mammary gland was able to synthesize the choline metabolites found in milk, but these metabolites may not be derived exclusively from uptake from maternal blood. We have established that the total choline concentration in rat milk is sevenfold higher than previously reported, with > 80% present as glycerophosphocholine and phosphocholine.

Animals↗

PubMed1992

Measurement of the formation of betaine aldehyde and betaine in rat liver mitochondria by a high pressure liquid chromatography-radioenzymatic assay.

A new assay procedure for measurement of rat liver mitochondrial choline dehydrogenase was developed. Oxidation of [methyl-14C]choline to [methyl-14C]betaine aldehyde and [methyl-14C]betaine was measured after isolating these compounds using HPLC. We observed that NAD+ was required for conversion of betaine aldehyde to betaine in rat liver mitochondria. In the absence of this cofactor, oxidation of choline led to the accumulation of betaine aldehyde. The apparent Km of the mitochondrial choline dehydrogenase for choline was 0.14-0.27 mM, which is significantly lower than previously reported. A partially purified preparation of choline dehydrogenase catalyzed betaine aldehyde formation only in the presence of exogenous electron acceptors (e.g., phenazine methosulfate). This preparation failed to catalyze the formation of betaine even in the presence of NAD+, indicating that betaine aldehyde dehydrogenase may be a separate enzyme from choline dehydrogenase.

Alcohol Oxidoreductases↗

PubMed1992

Choline: an important nutrient in brain development, liver function and carcinogenesis.

Choline is required to make certain phospholipids which are essential components of all membranes. It is a precursor for biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile methyl groups. Much attention has been given to the effect of supplemental choline upon brain function, i.e., enhancement of acetylcholine synthesis and release. In addition, choline supplements administered to rats in utero or shortly after birth permanently after brain function. The mechanisms for this effect is unknown and under investigation at this time. Healthy humans fed diets deficient in choline, and humans fed parenterally have decreased plasma choline concentrations and develop liver dysfunction that is similar to that seen in choline-deficient animals. In experimental animals, fatty liver occurs in choline deficiency because phosphatidylcholine synthesis is required for very low-density lipoprotein secretion. This accumulation of lipids in liver may explain why choline-deficient rats spontaneously develop hepatocarcinoma. We found that choline deficiency was associated with the accumulation of 1,2-diacylglycerol, an activator of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction.

Alanine Transaminase↗