Nonalcoholic fatty liver disease results from overconsumption and is a significant
and increasing cause of liver failure. The type of diet that is conducive to the development
of this disease has not been established, and evidence-based treatment options are
currently lacking. We hypothesized that the onset of hepatic steatosis is linked to
the consumption of a diet with a high fat content, rather than related to excess caloric
intake. In addition, we also hypothesized that fully manifested hepatic steatosis
could be reversed by reducing the fat percentage in the diet of obese mice. C57BL/6J
male mice were fed either a purified rodent diet containing 10% fat or a diet with
60% of calories derived from fat. A pair-feeding design was used to distinguish the
effects of dietary fat content and caloric intake on dietary-induced hepatic lipid
accumulation and associated injury. Livers were analyzed by quantitative reverse transcriptase
polymerase chain reaction for lipid metabolism-related gene expression. After 9 weeks,
mice on the 60%-fat diet exhibited more weight gain, insulin resistance, and hepatic
steatosis compared with mice on a 10%-fat diet with equal caloric intake. Furthermore,
mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis,
insulin resistance, and obesity when switched to a 10%-fat diet for an additional
9 weeks, independent of caloric intake. Quantitative reverse transcriptase polymerase
chain reaction revealed that transcripts related to both de novo lipogenesis and increased
uptake of free fatty acids were significantly up-regulated in mice pair-fed a 60%-fat
diet compared with 10%-fat-fed animals. Dietary fat content, independent from caloric
intake, is a crucial factor in the development of hepatic steatosis, obesity, and
insulin resistance in the C57BL/6J diet-induced obesity model caused by increased
uptake of free fatty acids and de novo lipogenesis. In addition, once established,
all these features of the metabolic syndrome can be successfully reversed after switching
obese mice to a diet low in fat. Low-fat diets deserve attention in the investigation
of a potential treatment of patients with nonalcoholic fatty liver disease.
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