It has been established that physiological/biochemical changes to the liver that are pathologically inert can enhance the hepatotoxic response caused by a second agent; this “two-hit” paradigm has been best exemplified in NAFLD and other fatty liver diseases.7, 8 One of the second “hits” in NAFLD appears to be diet composition; specifically a diet richer in saturated fats and cholesterol (a “Western” diet) appears to increase the risk of developing NASH.9 Based on these observations, several studies have investigated the mechanisms by which fat and fat type differentially mediate liver injury and potentially the transition from NAFLD to NASH. The current

prevailing hypothesis is that free fatty acid–mediated lipotoxicity is the culprit in NAFLD/NASH progression; however, Autophagy inhibitor the clinical evidence is far from conclusive at this time. The main purpose of the study by van Rooyen et al.10 is buy SP600125 to test the principle that cholesterol, which is also elevated in NASH livers,11 could also be the hepatotoxic

lipid. In short, this purpose was served very well in their work. The authors employed a mouse strain that contains a spontaneous mutation in the Alms1 gene (foz/foz mice). The phenotype of this mutant strain is analogous to those found in patients suffering from Alström syndrome in humans (e.g., obesity, insulin resistance, dyslipidemia, liver injury),12 which is accelerated by feeding of a selleck chemicals high-fat diet (HFD).13 The pathology in these mice is quite impressive and includes robust steatohepatitis with fibrosis as early as 12 weeks of HFD feeding.14 These changes correlated with an increase in both hepatic cholesterol ester (CE) (>50-fold) and free cholesterol

(FC) (≈4-fold). Given that cholesterol was only 0.2% of the diet, these data suggest that foz/foz mice somehow accumulate cholesterol. The remainder of the article is dedicated to determining the potential mechanisms. Hepatic free cholesterol can accumulate in the liver via several mechanisms: (1) increased uptake of dietary cholesterol and CEs, (2) increased de novo synthesis, and (3) decreased catabolism via bile acid synthesis and secretion (Fig. 1). HFD feeding in foz/foz mice altered two out of three of these pathways such that hepatic FC accumulation is favored. Specifically, key genes involved in uptake (CD36,14 low-density lipoprotein receptor) and hydrolysis of CE (CE hydrolase) are up-regulated by HFD in foz/foz mice. Furthermore, key genes involved in bile acid synthesis (CYP7A1) and secretion (bile salt export pump), as well as cholesterol secretion (ABCG5/8), were all dramatically down-regulated in the foz/foz strain compared with all other groups. An interesting aspect of this work is that the phenotype in the foz/foz mice fed HFD was so dramatically different than all other groups (wild-type [WT] chow, WT HFD, and foz/foz chow).