Phosphatidylcholine protects against steatosis in mice but not non-alcoholic steatohepatitis

University of Alberta, Edmonton, Canada.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 07/2011; 1811(12):1177-85. DOI: 10.1016/j.bbalip.2011.06.021
Source: PubMed


Several studies suggest that low levels of hepatic phosphatidylcholine (PC) play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). CTP: phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for PC biosynthesis. Liver-specific elimination of CTα (LCTα(-/-)) in mice fed a chow diet decreases very-low-density lipoprotein secretion, reduces lipid efflux from liver, and causes mild steatosis. We fed LCTα(-/-) mice a high fat diet to determine if impaired PC biosynthesis played a role in development of NASH. LCTα(-/-) mice developed NASH within one week of high fat feeding. Hepatic CTα deficiency caused hepatic steatosis, a 2-fold increase in ceramide mass, and a 20% reduction in PC content. In an attempt to prevent NASH, LCTα(-/-) mice were either injected daily with CDP-choline or fed the high fat diet supplemented with betaine. In addition, LCTα(-/-) mice were injected with adenoviruses expressing CTα. CDP-choline injections and adenoviral expression of CTα increased hepatic PC, while dietary betaine supplementation normalized hepatic triacylglycerol but did not alter hepatic PC mass in LCTα(-/-) mice. Interestingly, none of the treatments normalized hepatic ceramide mass or fully prevented the development of NASH in LCTα(-/-) mice. These results show that normalizing the amount of hepatic PC is not sufficient to prevent NASH in LCTα(-/-) mice.

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    • "Recent evidence demonstrates that ASMase regulates key mechanisms involved in steatosis, fibrosis and lipotoxicity, including endoplasmic reticulum (ER) stress, autophagy and lysosomal membrane permeabilization (LMP), which contribute to ASH and NASH (Figure 1) [6] [17] [18]. Disturbed methionine metabolism, exemplified by decreased S-adenosyl-L-methionine (SAM, also abbreviated as SAMe or AdoMet) and/or increased S-adenosylhomocysteine (SAH) and homocysteine (Hcy) levels, and phosphatidylcholine (PC) depletion control key liver functions and have been described in experimental models of steatohepatitis and patients [19] [20] [21] [22] [23] [24] [25] [26]. Moreover, emerging data link ASMase activation with modulation of SAM and PC homeostasis, suggesting that targeting ASMase and restoration of methionine metabolism and PC levels may be a promising strategy for the treatment of ASH/NASH. "
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    ABSTRACT: Steatohepatitis (SH) is an intermediate stage of fatty liver disease and one of the most common causes of chronic liver disease worldwide that may progress to cirrhosis and liver cancer. SH encompasses alcoholic and nonalcoholic steatohepatitis, the latter being of particular concern due to its association with obesity and insulin resistance and a major cause of liver transplantation. The molecular mechanisms governing the transition from steatosis to SH are not fully understood. Here we discuss emerging data indicating that acid sphingomyelinase (ASMase), a specific mechanism of ceramide generation, is required for the activation of key pathways that regulate steatosis, fibrosis and lipotoxicity, including endoplasmic reticulum stress, autophagy and lysosomal membrane permeabilization. Moreover, ASMase modulates alterations of methionine cycle and phosphatidylcholine homeostasis, two crucial events involved in SH that regulate methylation reactions, antioxidant defense and membrane integrity. These new findings suggest that targeting ASMase in combination with restoration of methionine metabolism and phosphatidylcholine levels may be of utility in the treatment of SH.
    Journal of Hepatology 10/2014; 62(1). DOI:10.1016/j.jhep.2014.09.023 · 11.34 Impact Factor
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    • "These observations can be explained by a reduction in hepatic secretion of VLDL particles in the pemt 2/2 mice [16]. Similarly, deletion of hepatic CTa impairs VLDL secretion and increases susceptibility to diet-induced steatosis [17] [18]. These results and others highlight the role of PC synthesis in the maintenance of hepatic lipid metabolism. "
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    ABSTRACT: Folate is an essential B vitamin required for the maintenance of AdoMet-dependent methylation. The liver is responsible for many methylation reactions that are used for post-translational modification of proteins, methylation of DNA, and the synthesis of hormones, creatine, carnitine, and phosphatidylcholine. Conditions where methylation capacity is compromised, including folate deficiency, are associated with impaired phosphatidylcholine synthesis resulting in non-alcoholic fatty liver disease and steatohepatitis. In addition, folate intake and folate status have been associated with changes in the expression of genes involved in lipid metabolism, obesity, and metabolic syndrome. In this review, we provide insight on the relationship between folate and lipid metabolism, and an outlook for the future of lipid-related folate research. © 2013 BioFactors, 2013.
    BioFactors 05/2014; 40(3). DOI:10.1002/biof.1154 · 4.59 Impact Factor
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    • "Thus betaine, choline, myo-inositol, methionine, and carnitine are among the important lipotropes, that is, compounds that limit excess hepatic fat deposits [8]. Nutritive supplements like phosphatidyl choline can protect against steatosis in mice [9]. Other food compounds have been tested for their ability to limit hepatic steatosis. "
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    ABSTRACT: The main purpose of the present research was to study the protective effect of Nigella sativa crude oils (NCO) extracted from plain and γ-irradiated seeds towards inflammatory fatty liver (steatohepatitis). The protective effect of the oils was tested during induction of inflammatory fatty liver in rats through feeding high fructose diet. Biochemical analyses including plasma lipids, tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) levels and liver fat and liver function tests were carried out to determine the efficiency of the oils. Results showed that fatty liver control group exhibited significant dyslipidemia, high plasma TNF-α and MDA along with significant high liver triglycerides and cholesterol and liver dysfunction compared to control normal. Oral administration of NCO produced significant improvement of all parameters. No significant change in all biochemical parameters was noticed when the group given γ-irradiated NCO was compared with that given the plain oil. Lipid analysis by GC showed that linoleic and oleic where the most abundant fatty acids constituting NCO. Volatile oils' contents were 0.1 wt% of NCO; p-cymene and thymoquinone being the major constituents. Administration of NCO from plain or γ-irradiated seeds produced similar and significant, but not complete, prevention of inflammatory fatty liver. Practical applications: This investigation revealed that the crude oil of Nigella sativa seed may potentially be used as dietary supplement for prevention of inflammatory fatty liver. The study also showed the chemical composition of the fixed and volatile oil fractions of the Egyptian N. sativa seeds that may be useful for further studies.
    European Journal of Lipid Science and Technology 07/2013; 115(7). DOI:10.1002/ejlt.201200256 · 1.81 Impact Factor
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