choline synthesis (8). Importantly, unlike human or other diet-induced rodent models of NAFLD, rodents fed MCD diets lose weight (due to a vastly lower caloric intake) and do not become insulin resistant (9, 10). This is in contrast to the typical human with NASH, who is obese and insulin resistant. The source of dietary fat used in MCD diets can alter the phenotype. By using a polyunsaturated dietary fat source, liver fat oxidation, induction of proinflammatory genes and inflammation can be increased (relative to a more saturated dietary fat) though this does not necessarily result in increased liver damage (11). In a different study, olive oil reduced liver TAG accumulation while fish oil reduced liver cholesterol levels (12).

CD Diets
CD diets offer the potential advantage that they also increase liver fat levels, and unlike MCD diets, increase body weight, induce dyslipidemia and cause insulin resistance (13). The mechanisms involved with liver fat accumulation may be different from those at work during MCD diet feeding (14) and liver fat accumulation, liver damage and inflammation is less severe than with MCD diets (13). Interestingly, choline deficiency in the context of a high fat diet can improve glucose tolerance in mice (15).

High- Fat Diets
High-fat diets (HFD) are well-known to increase body weight, body fat and induce insulin resistance in rodent models. HFD can also increase liver fat levels quite rapidly (within days) and before significant increases in peripheral fat deposition occur (16). Such rapid liver fat accumulation is associated with hepatic insulin resistance (16). Chronically, HFD-induced liver fat accumulation may not follow a linear progression and liver fat levels may actually decrease, then increase again during prolonged HFD feeding (17). When fed for equal lengths of time, HFD feeding results in 10-fold lower liver fat levels compared to what accumulates on an MCD diet (18). In general, HFD feeding does not produce liver fibrosis and only mild steatosis as compared to MCD diets (3).

In a recent issue of Diabetes, Raubenheimer et al., used a combination of a choline-deficient and HFD to examine the effects of excess liver fat on the insulin resistance and glucose tolerance that accompanies diet-induced obesity (15). C57Bl/6 mice were fed either high-fat or low-fat diets with or without choline. Choline deficiency did not affect body weight gain or adipose tissue depot weight but did increase liver triglyceride levels in both low- and high-fat diets. The control HFD increased body weight as well as fasting plasma insulin and glucose levels (versus control low-fat fed animals), suggesting that the mice were becoming insulin resistant. Interestingly, mice fed the choline-deficient HFD had reduced insulin levels compared to those fed the HFD with choline. Furthermore, mice fed the choline-deficient HFD had improved glucose tolerance compared to mice fed the HFD with choline. These researchers also found that choline-deficiency in the context of a HFD induced the expression of genes for hepatic enzymes involved with FFA esterification to triacylglycerol while gene expression for enzymes involved with fatty acid synthesis and oxidation was unchanged.

The authors concluded that the redirection of fatty acids into hepatic triglyceride storage may be an initial protective mechanism to lower hepatic intracellular fatty acid concentrations. Since elevated intracellular fatty acids are thought to play a causal role in hepatic insulin resistance, their storage as triglyceride would serve to maintain liver insulin sensitivity. Whether or not longer-term feeding of a choline-deficient HFD would eventually lead to impaired insulin sensitivity is unknown.

Reference List
1.   Zafrani ES. Non-alcoholic fatty liver disease: an emerging pathological spectrum. Virchows Arch 444: 3-12, 2004.
2.   Marchesini G and Babini M. Nonalcoholic fatty liver disease and the metabolic syndrome. Minerva Cardioangiol 54: 229-239, 2006.
3.   Anstee QM and Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 87: 1-16, 2006.
4.   Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A and Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129: 113-121, 2005.
5.   Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM and Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40: 1387-1395, 2004.
6.   Sahai A, Malladi P, Melin-Aldana H, Green RM and Whitington PF. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol 287: G264-G273, 2004.
7.   Weltman MD, Farrell GC and Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology 111: 1645-1653, 1996.
8.   Yao ZM and Vance DE. Reduction in VLDL, but not HDL, in plasma of rats deficient in choline. Biochem Cell Biol 68: 552-558, 1990.
9.   Kirsch R, Clarkson V, Shephard EG, Marais DA, Jaffer MA, Woodburne VE, Kirsch RE and Hall PL. Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol 18: 1272-1282, 2003.
10.   Rinella ME and Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol 40: 47-51, 2004.
11.   Lee GS. Yan, JS, Ng RK, Kakar S and Maher JJ.  Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury.  J Lipid Res 48:1885-1896, 2007.
12.   Hussein O, Grosovski M, Lasri E, Svlab S, Ravid U and Assy N.  Monounsaturated fat decreases hepatic lipid contgent in non-alcoholic fatty liver disease in rats. World J Gastroenterol  13: 361-38, 2007.
13.   Vetelainen R, van Vliet A, and can Gulik TM.  Essential pathogenic and metabolic differences in steatosis induced by choline or methionine-choline deficient diets in a rat model.  J Gastroenterol Hepatol  22:1526-1533, 2007.
14.   Kulinski A, Vance DE and Vance JE. A choline-deficient diet in mice inhibits neither the CDP-choline pathway for phosphatidylcholine synthesis in hepatocytes nor apolipoprotein B secretion. J Biol Chem 279: 23916-23924, 2004.
15.   Raubenheimer PJ, Nyirenda MJ and Walker BR. A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet. Diabetes 55: 2015-2020, 2006.
16.   Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ and Shulman GI. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279: 32345-32353, 2004.
17.   Gauthier MS, Favier R and Lavoie JM. Time course of the development of non-alcoholic hepatic steatosis in response to high-fat diet-induced obesity in rats. Br J Nutr 95: 273-281, 2006.
18.   Romestaing C, Piquet MA, Bedu E, Rouleau V, Dautresme M, Hourmand-Ollivier I, Filippi C, Duchamp C, and Sibille B. Long term highly saturated fat diet does not induce NASH in Wistar rats.  Nutr Metab  21:4:4, 2007.