Many of the genes that show diet-independent responses to Cyp1b1 deletion are regulated by PPARα and affect steps in fatty acid homeostasis (Tables 2 and 3). Examples include CD36, which contributes to triglyceride homeostasis through fatty acid transport across the plasma membrane [43], cytochrome P450 4a14 (Cyp4a14), which hydroxylates long chain fatty acids [44] and several genes involved in peroxisome function, including the peroxisomal transporter 11 (Pex11a) and Acyl CoA transferase I (Acot 1) [45–46]. Several other gene changes that enhance triglyceride accumulation are stimulated by PPARα activation, but are reversed in Cyp1b1-ko mice. These include Vldlr (increases triglyceride uptake), Cidec/Fsp27 (stabilizes lipid droplets) and Klf6 (promotes adipocyte differentiation) [47–49]. Lpin2, a phosphatidic acid phosphatase that activates PPARα, is also decreased by Cyp1b1 deletion [50]. G0s2, an inhibitor of adipose triglyceride lipase (Pnpla2) is suppressed by PPARα activation [51] and Cyp1b1 deletion. The histological data (Figure 5) suggests that these effects on the control of fatty acid metabolism combine to suppress lipid droplets in Cyp1b1-ko livers as shown in Figure 6A.
