Familial partial lipodystrophic syndrome 3 (FPLD3) is associated with mutations in the transcription factor PPAR. One of these mutations, the P467L, confers a dominant negative effect. We and others have previously investigated the pathophysiology associated to this mutation using a humanised mouse model that recapitulated most of the clinical symptoms observed in human patients under different experimental conditions. One of the key clinical manifestations observed both in humans and mouse models is the ectopic accumulation of fat in the liver. Here, we dissect the molecular mechanisms that contribute to the excessive accumulation of lipids in the liver and characterise the negative effect of this PPAR mutation on the activity of PPAR in vivo when activated by fibrates. P465L mice have increased levels of insulin and free fatty acids (FFA), exhibit decreased levels of Very Low Density Lipoproteins (VLDL) when fed high fat diet (HFD) and partial impaired response to the hypolipidemic action of WY14643. This indicates that the deleterious effects of P465L-PPAR mutation may be augmented by their collateral negative effect on PPAR function.Wellcome Trust, MRC MDU (MC_UU_12012/2), FP7-MITIN (Integration of the System Models of Mitochondrial Function and Insulin Signaling and its Application in the Study of Complex Diseases) (Grant Agreement 223450) and H2020 EPoS (Elucidating Pathways of Steatohepatitis) (Grant Agreement 634413). Disease Model Core, Biochemistry Assay Lab and the Histology Core are funded by MRC_MC_UU_12012/5 and a Wellcome Trust Strategic Award [100574/Z/12/Z
