Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease (original) (raw)

Mice with peripheral insulin resistance due to adipose- and muscle-specific GLUT4 double knockout showed increased DNL accompanied by hepatic elevation of SREBP-1c and acetyl-CoA carboxylase (12). However, in these mice, increased DNL did not result in increased TAG level in the liver, nor did it increase steady-state serum levels of TAGs or NEFAs; this may be the result of a compensatory enhancement of peripheral fatty acid usage. Unlike in this animal model, such compensation is assumed to be insufficient in human subjects with type 2 diabetes (13). The reduced use of fatty acids in peripheral tissues in combination with elevated DNL may contribute to TAG accumulation in the livers of subjects with NAFLD. Muscle exercise is effective in reducing TAG accumulation in the liver not only by improving insulin resistance but also by enhancing peripheral fatty acid disposal.

The accumulation of TAGs in the liver results from an imbalance among the uptake, synthesis, export, and oxidation of fatty acids. In type 2 diabetes, secretion of VLDL is increased due to insulin resistance (14). It has been reported, however, that in NAFLD, VLDL secretion is not increased compared with secretion in controls (5). Because of methodological differences, these results cannot be directly compared. Secretion rates of hepatic VLDL should be quantified in hyperinsulinemic subjects with and without hepatic steatosis. β-oxidation of fatty acids in the liver was found to be increased in patients with NASH (15). However, the increase is not sufficient for overcoming elevated rates of hepatic TAG synthesis. The increase in NEFA oxidation may account for the apparent oxidative stress that causes hepatic injury in NAFLD.

In the study by Donnelly et al. (2), considerable variation was present in liver TAG level as well as in the degrees of inflammation and fibrosis in the liver. In some cases of NASH, the amount of accumulated fat in the liver decreased as the disease progressed to cirrhosis (16). In addition, the degree of liver damage may influence lipid metabolism and apparent insulin sensitivity (15, 17). Thus, to clarify the earliest events in TAG accumulation precisely, metabolic analysis of patients with simple fatty liver (i.e., without hepatitis) is needed.

Donnelly et al. (2) show that the contributions of fatty acid sources of TAG in VLDL are almost the same as those for the TAG pool in the liver. Although these findings result from studies of NAFLD patients, the approach used will allow us to further investigate this in vivo biochemistry at various stages in the development of NAFLD, as well as the effects of diet, exercise, and pharmacological therapies on the disease.