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The pregnane X receptor (PXR) initially isolated as a nuclear receptor regulating xenobiotic and drug metabolism and elimination, seems to play an endobiotic role by affecting lipid homeostasis. In mice, PXR affects lipid homeostasis and increases hepatic deposit of triglycerides. In this study, we show that, in human hepatocyte, PXR activation induces an increase of de novo lipogenesis through the up-regulation of S14. S14 was first identified as a thyroid-responsive gene and is known to transduce hormone-related and nutrient-related signals to genes involved in lipogenesis through a molecular mechanism not yet elucidated. We demonstrate that S14 is a novel transcriptional target of PXR. In addition, we report an increase of fatty acid synthase (FASN) and adenosine triphosphate citrate lyase genes expression after PXR activation in human hepatocyte, leading to an increase of fatty acids accumulation and de novo lipogenesis. RNA interference of the expression of S14 proportionally decreases the FASN induction, whereas S14 overexpression in human hepatic cells provokes an increase of fatty acids accumulation and lipogenesis. These results demonstrate for the first time that xenobiotic or drug-activated PXR promote aberrant hepatic de novo lipogenesis via activation of the nonclassical S14 pathway. In addition, these data suggest that the up-regulation of S14 by PXR may promote aberrant hepatic lipogenesis and hepatic steatosis in human hepatocytes. (HEPATOLOGY 2009;49:2068-2079 L ipid homeostasis is achieved by complex physiological mechanisms. Disruptions of lipid formation and catabolism have been implicated in various metabolic diseases such as obesity and diabetes. Hepatic lipid homeostasis is tightly maintained by balanced lipid synthesis, catabolism (␤-oxidation), and uptake/secretion. The liver is a major organ for lipogenesis and expresses high levels of lipogenic enzymes, such as fatty acid synthase (FASN), adenosine triphosphate citrate lyase, and stearoyl-CoA desaturase-1. Several receptors have been implicated in lipid homeostasis, such as the liver X receptor alpha and beta isoforms (LXR␣ and LXR␤ 1 ) or thyroid hormone receptor (TR 2 ). The effect of LXR on lipogenesis involves both direct and indirect mechanisms. LXR/retinoid X receptor (RXR) heterodimers bind lipogenic gene promoters, such as FASN, or regulate lipogenic gene expression by controlling levels of sterol regulatory element binding protein (SREBP)-1c, a transcriptional factor known to regulate the expression of a battery of lipogenic enzymes. [3][4][5] In addition, thyroid hormone (T3) is known to regulate hepatic lipogenesis after binding to TR, which binds to the target DNA sequence thyroid response element (TRE), leading to an increased transcription of several genes involved in lipogenesis. 6,7 The pregnane X receptor (PXR), initially isolated as a nuclear receptor regulating xenobiotic and drug metabolism and elimination, 8 plays an endobiotic role by affect-