Specific Contribution of Methionine and Choline in Nutritional Nonalcoholic Steatohepatitis

Abstract

The pathogenesis and treatment of nonalcoholic steatohepatitis (NASH) are not well established. Feeding a diet deficient in both methionine and choline (MCD) is one of the most common models of NASH, which is characterized by steatosis, mitochondrial dysfunction, hepatocellular injury, oxidative stress, inflammation, and fibrosis. However, the individual contribution of the lack of methionine and choline in liver steatosis, advanced pathology and impact on mitochondrial S-adenosyl-Lmethionine (SAM) and glutathione (GSH), known regulators of disease progression, has not been specifically addressed. Here, we examined the regulation of mitochondrial SAM and GSH and signs of disease in mice fed a MCD, methionine-deficient (MD), or choline-deficient (CD) diet. The MD diet reproduced most of the deleterious effects of MCD feeding, including weight loss, hepatocellular injury, oxidative stress, inflammation, and fibrosis, whereas CD feeding was mainly responsible for steatosis, characterized by triglycerides and free fatty acids accumulation. These findings were preceded by MCD-or MD-mediated SAM and GSH depletion in mitochondria due to decreased mitochondrial membrane fluidity associated with a lower phosphatidylcholine/phosphatidylethanolamine ratio. MCD and MD but not CD feeding resulted in increased ceramide levels by acid sphingomyelinase. Moreover, GSH ethyl ester or SAM therapy restored mitochondrial GSH and ameliorated hepatocellular injury in mice fed a MCD or MD diet. Thus, the depletion of SAM and GSH in mitochondria is an early event in the MCD model of NASH, which is determined by the lack of methionine. Moreover, therapy using permeable GSH prodrugs may be of relevance in NASH.

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia–reperfusion injury

“…Choline is an essential nutrient required for efficient phosphatidylcholine synthesis necessary for the packaging and export of VLDL particles to extrahepatic organs. Feeding mice a CD diet results in hepatic steatosis with predominant TG content and unchanged cholesterol levels compared to chow-fed mice (Fig 1A), consistent with previous reports [10,20,21]. In contrast, increased hepatic cholesterol levels but unchanged TG content are observed in mice fed the HC diet ( Fig 1B).…”

“…Importantly, while this particular pool of GSH decreased further in ob/ob mice during I/R, both therapies significantly increased the JHEPAT-D-10-00907-R Llacuna et al, 15 mitochondrial GSH levels in ob/ob mice following I/R (Fig 7), in agreement with the effect of atorvastatin and YM-53601 on the mitochondrial cholesterol content (Fig 5C). Similar protective findings were observed when the pool of mGSH is restored by GSH ethyl ester (not shown), a permeable form of GSH [21]. Consistent with the reversal of the mitochondrial GSH stores, atorvastatin and the squalene synthase inhibitor attenuated oxidative stress determined by the increase in MDA levels ( Supplemental Fig 3).…”

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

“…GSH levels are decreased in NASH patients [25,26] and in mice treated with a MCD diet [26]. Restoring mitochondrial GSH to normal levels by the administration of GSH precursors prevents the establishment of inflammation in the MCD diet model [36]. A marked decrease of MRC activity have been evidenced in patients with NAFLD [37], and liver mitochondrial dysfunction seems to be an early pathogenetic step that precedes fatty liver in rats [38].…”

The follicular microenviroment as a predictor of pregnancy: MALDI-TOF MS lipid profile in cumulus cells

“…It was identified through the two ions found in this group with m/z 750.4191 and 806.4842. In cells, PS is located exclusively in the intracellular environment (Caballero et al), which plays an important role because many intracellular proteins, such as protein kinases, require PS for proper activation and/or location [7,25,31]. Moreover, PS has also been described as a marker of apoptosis [4,15,16].…”