This study joins a growing body of evidence linking cholesterol to fatty liver and NASH. C57BL/6J mice fed a high fat, high cholesterol diet developed profound hepatic steatosis, substantial Protein Tyrosine Kinase inhibitor inflammation and perisinusoidal fibrosis (steatohepatitis), associated with adipose tissue inflammation and a reduction
in plasma adiponectin levels, while mice fed a high fat diet without cholesterol only developed simple steatosis.3 Addition of dietary cholesterol to a high-fat, high-carbohydrate, “diabetogenic diet” led to increased hepatic steatosis, inflammation and fibrosis in LDL receptor deficient mice.4 Also the addition of cholesterol to the diet of Alms1 mutant (foz/foz) mice, which are obese and insulin resistant, led to accumulation of hepatic free cholesterol, hepatocyte apoptosis, macrophage recruitment and liver fibrosis.5 Gefitinib datasheet Administration of a liver X receptor (LXR) agonist to hyperlipidemic mice with NASH led to a reduction in hepatic cholesterol and an increase in hepatic triglyceride: this change in hepatic lipid patterns actually led to a decrease in hepatic inflammation, thus dissociating the effects of triglycerides (responsible
for most of the observed “steatosis”) from the effects of cholesterol (likely responsible for the inflammation).6 Human data are also emerging to support a role for dietary cholesterol in the development of progressive NASH or cirrhosis. In a large, nationally-representative epidemiological study in the USA, dietary cholesterol consumption was independently associated with the development of cirrhosis.7 Finally, recent, pilot clinical trials of ezetimibe, Ribonucleotide reductase which inhibits intestinal cholesterol absorption, in humans with NASH have found improvements
in hepatic inflammation and steatosis, although these studies were not randomized or controlled.8,9 Could cholesterol be the critical factor responsible for the development of NASH in a unifactorial model of the disease, as shown in Figure 1? Such a model could certainly explain most of the known associations of NASH. Factors such as diet, lifestyle and obesity are either directly or indirectly related to cholesterol intake. Other factors such as insulin resistance and adipokines levels could modify cholesterol-induced liver damage. The model also leads to testable hypotheses: if cholesterol-induced liver injury is the sine qua non of NASH, then NASH should not occur in the absence of cholesterol-induced liver injury, even if disease modifiers such as obesity, steatosis, insulin resistance and abnormal adipokines profiles are present. Finally, the model would direct attention to mechanisms of cholesterol-induced liver damage, such as macrophage10 or stellate cell11 activation, and lead to interventions directed against these mechanisms. Analogies to cholesterol-induced damage in atherosclerosis might be particularly relevant.