Peroxisome proliferator activated-receptor (PPAR) isoforms, α and γ, function as important coregulators of energy (lipid) homeostasis. PPARα regulates fatty acid oxidation primarily in liver and to a lesser extent in adipose tissue, whereas PPARγ serves as a key regulator of adipocyte differentiation and lipid storage. Of the two PPARγ isoforms, PPARγ1 and PPARγ2 generated by alternative splicing, PPARγ1 isoform is expressed in liver and other tissues, whereas PPARγ2 isoform is expressed exclusively in adipose tissue where it regulates adipogenesis and lipogenesis. Since the function of PPARγ1 in liver is not clear, we have, in this study, investigated the biological impact of overexpression of PPARγ1 in mouse liver. Adenovirus-PPARγ1 injected into the tail vein induced hepatic steatosis in PPARα−/− mice. Northern blotting and gene expression profiling results showed that adipocyte-specific genes and lipogenesis-related genes are highly induced in PPARα−/− livers with PPARγ1 overexpression. These include adipsin, adiponectin, aP2, caveolin-1, fasting-induced adipose factor, fat-specific gene 27 (FSP27), CD36, Δ9desaturase, and malic enzyme among others, implying adipogenic transformation of hepatocytes. Of interest is that hepatic steatosisper se, induced either by feeding a diet deficient in choline or developing in fasted PPARα−/− mice, failed to induce the expression of these PPARγ-regulated adipogenesis-related genes in steatotic liver. These results suggest that a high level of PPARγ in mouse liver is sufficient for the induction of adipogenic transformation of hepatocytes with adipose tissue-specific gene expression and lipid accumulation. We conclude that excess PPARγ activity can lead to the development of a novel type of adipogenic hepatic steatosis.

Adipocyte-specific Gene Expression and Adipogenic Steatosis in the Mouse Liver Due to Peroxisome Proliferator-activated Receptor γ1 (PPARγ1) Overexpression