Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1

University of Arkansas at Little Rock, Little Rock, Arkansas, United States
The Journal of Lipid Research (Impact Factor: 4.42). 11/2006; 47(10):2280-90. DOI: 10.1194/jlr.M600198-JLR200
Source: PubMed


Lipogenic diets that are completely devoid of methionine and choline (MCD) induce hepatic steatosis. MCD feeding also provokes systemic weight loss, for unclear reasons. In this study, we found that MCD feeding causes profound hepatic suppression of the gene encoding stearoyl-coenzyme A desaturase-1 (SCD-1), an enzyme whose regulation has significant effects on metabolic rate. Within 7 days of MCD exposure, hepatic SCD-1 mRNA decreased to nearly undetectable levels. By day 21, SCD-1 protein was absent from hepatic microsomes and fatty acids showed a decrease in monounsaturated species. These changes in hepatic SCD-1 were accompanied by signs of hypermetabolism. Calorimetry revealed that MCD-fed mice consumed 37% more energy than control mice (P = 0.0003). MCD feeding also stimulated fatty acid oxidation, although fatty oxidation genes were not significantly upregulated. Interestingly, despite their increased metabolic rate, MCD-fed mice did not increase their food consumption, and as a result, they lost 26% of their body weight in 21 days. In summary, MCD feeding suppresses SCD-1 in the liver, which likely contributes to hypermetabolism and weight loss. MCD feeding also induces hepatic steatosis, by an independent mechanism. Viewed together, these two disparate consequences of MCD feeding (weight loss and hepatic steatosis) give the appearance of an unusual form of lipodystrophy.

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Available from: Lorenzo Arnaboldi, Apr 16, 2015
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    • "In addition to the accumulation of hepatic triglycerides in response to choline deficiency and lipogenesis [22] [23], and impaired antioxidant defences in response to methionine deficiency , induction of CYP2E1 (or CYP4A) [24] and C/EBPb [17] may induce oxidative stress in the MCD model of steatohepatitis. "
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    ABSTRACT: Background & Aims Perpetuate liver inflammation is crucial in the pathogenesis of non-alcoholic steatohepatitis (NASH). Expression of CXCL10, a pro-inflammatory cytokine, correlates positively with obesity and type 2 diabetes. Whether CXCL10 plays a role in NASH was unknown. We aimed to investigate the functional and clinical impact of CXCL10 in NASH. Methods Gene-deleted CXCL10 (CXCL10-/-) and C57BL/6 wildtype (WT) mice were fed methionine- and choline-deficient (MCD) diets for 4 or 8 weeks. In other experiments, we injected neutralizing anti-CXCL10 mAb into MCD-fed WT mice. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 control subjects. Results WT mice fed MCD diet developed steatohepatitis with higher hepatic CXCL10 expression. CXCL10-/- mice were refractory to MCD-induced steatohepatitis. We further revealed that CXCL10 was associated with the induction of important pro-inflammatory cytokines (TNF-α, IL-1β and MCP-1) and activation of NF-κB pathway. CXCL10 was linked to steatosis through up-regulation of lipogenic factors SREBP-1c and LXR, and also to oxidative stress (up-regulation of CYP2E1 and C/EBPβ). Blockade of CXCL10 protected against hepatocyte injury in vitro and steatohepatitis development in mice. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients. Conclusions We demonstrate for the first time that CXCL10 plays a pivotal role in pathogenesis of experimental steatohepatitis. CXCL10 maybe a potential non-invasive biomarker for NASH patients.
    Full-text · Article · Jul 2014 · Journal of Hepatology
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    • "Small amounts of methionine may increase the hepatic flow of fatty acids via b-oxidation, which in turn increases total body energy expenditure and promotes mitochondrial uncoupling. The increase in the expression of mRNA UCP, influenced by methionine restriction, is followed by a sharp decrease in liver ATP levels in rats (Rizki et al., 2006). According to Hasek et al. (2010), the increase in the expression of mRNA UCP, involved in lipid metabolism and in the glucose cycle, suggests a mechanism of nutrient detection, which compensates the dietary restriction of methionine through the integrated effects of energy homeostasis. "
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    Full-text · Article · Feb 2013 · Livestock Science
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    • "Optimal methionine intake for developing enlarged fatty liver in mice fed MCDHFD Consistent with the results of previous studies on MCDD (Rizki et al. 2006; Rinella et al. 2008), C57BL/6J mice fed MCDHFD for 3 weeks developed a significantly high level of plasma ALT (486 AE 6.6 U/l) with accompanying significant loss of epididymal fat pad mass and significant loss of body weight (Table 1). However, the animals did not show a steady decrease in activity levels during the course of the 3 weeks, and their calorie intake remained at approximately 10 kcal per day. "
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    Preview · Article · Jan 2013 · International Journal of Experimental Pathology
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