Serine palmitoyl-CoA transferase (SPT) is the key and conserved enzyme in sphingolipid de novo biosynthesis. Mice totally lacking SPT are embryonic lethal. Previously, we reported that Sptlc2-Flox mice have almost no liver SPT activity after injecting adenovirus associated virus (AAV)-Cre recombinase, and these mice significantly decrease plasma SM levels (Li et al. J. Biol. Chem, 2009). We expected the same results, when we crossed Sptlc2-Flox with albumin-Cre transgenic mice. To our surprise, we observed a totally unexpected outcome. The liver-specific Sptlc2 deficiency dramatically increases plasma free cholesterol, phospholipid, and sphingomyelin levels. Lipoprotein X is the dominant lipoprotein in the blood. The deficient mice have dramatically higher plasma bilirubins than controls and have severe jaundice. Image from electronic microscope indicated that Sptlc2 deficiency significantly decreases microvilli on bile canaliculus. Moreover, hepatocytes from the deficient mice totally lose their polarity, indicated by apical proteins (for instance, BSEP) are co-localized with base membrane proteins (for instance, ABCA1 and NTCP). In conclusion, inhibition of liver SPT at the early stage of life leads losing cell polarity.