Despite minimal expression in mouse hepatocytes, Cyp1b1 deletion substantially impacts fatty acid homeostasis and the expression of associated liver genes. This is accompanied by extensive suppression of obesity that is induced by a high fat diet, as well as the subsequent liver enlargement and lipid infiltration that precedes NASH [30] (Figures 1, 2, 3 and 5). Although the DIO response is delayed, it is similarly suppressed in the Cyp1b1-ko female mice. The depletion of lipid droplets in Cyp1b1-ko livers was consistently observed, even when adiposity suppression was modest (Figure S4B). The hepatocytes of the Cyp1b1-ko mice are primarily affected within the sinusoidal region, where glycogen granules accumulate, replacing the triglycerides of lipid droplets (Figures 5 and Figure S4A). This replacement is consistent with the gene expression changes (Tables 2 and 3, Figure 7), particularly the near complete suppression of constitutive PPARα activity and Scd1 on the HFD. Scd1 re-directs fatty acid metabolism from mitochondrial oxidation to storage as triglycerides. Adenoviral expression of human SCD1 in these Cyp1b1-ko mice restored the WT level of obesity [38].
