Abstract
While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.
Highlights
The poor reputation of dietary cholesterol traces back to its supposed promoting role in the development of atherosclerosis [1]
The high fat diet-induced weight gain could be attributed to an increase in fat mass (Figure 1B) while the fat-free mass remained largely unaltered
In our current study we showed that dietary cholesterol induced hepatic steatosis and non-alcoholic fatty liver disease (NAFLD)
Summary
The poor reputation of dietary cholesterol traces back to its supposed promoting role in the development of atherosclerosis [1]. The impact of dietary cholesterol on atherosclerosis has apparently been largely overestimated [2,3] and more recent recommendations for cardio-protective diets do not include the previously suggested radical reduction of cholesterol intake [4]. From the point of view of atherosclerosis, dietary cholesterol might be less relevant than previously assumed, it has reentered the focus of interest because of its potential role in the progression of non-alcoholic fatty liver disease (NAFLD) [5,6]. The disease pattern ranges from fully reversible blunt steatosis (NAFL) to a chronically progressive disease (non-alcoholic steatohepatitis, NASH) that is characterized by varying degrees of hepatocyte death, inflammation, and fibrosis and may result in liver cirrhosis, hepatocellular carcinoma, and terminal organ failure [9]. A number of independent animal experimental studies showed that enrichment of a high fat diet with 0.2 to 2% cholesterol resulted in a rapid progression from blunt steatosis to a NASH-like phenotype with ballooning, infiltration with inflammatory cells, and fibrosis [10,11,12,13,14]
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