These oxysterols in turn activate LXR, and subsequently up-regulate expression of its target genes involved in cholesterol, fatty acid, and triglyceride biosynthesis. In addition, 25HC activates LXR, down regulates newly synthesized cholesterol biosynthesis by inhibiting HMGR expression and increases ABCA1 mediated cholesterol secretion from the cells. Oxysterols can be further sulfated to form oxysterol sulfates, such as 25HC3S and 25HCDS, which inactivate LXRs, suppress SREBP-1c processing, indicating that these sulfated oxysterols decrease intracellular lipid levels by inhibiting their biosynthesis. It is well known that the alternative pathway of bile acid biosynthesis involves the transporting of cholesterol into the mitochondria where the cholesterol is hydroxylated and then converted to bile acids. However, the recent reports that oxysterols and oxysterol sulfates generated by this pathway play an important role in lipid metabolism, inflammatory responses, and cell proliferation, indicating that this pathway is far more than only cholesterol degradation or bile acid biosynthesis. It has been reported that 7-ketocholesterol can be sulfated to be 7-ketocholesterol 3 sulfate ; 24-hydroxycholesterol, 24-hydroxycholesterol 3-sulfate ; 24,25-epoxycholesterol, 24,25-epoxycholesterol 3-sulfate; cholesterol, cholesterol sulfate. Cholesterol sulfate has been reported to inhibit gluconeogenesis but 25HCDS does not. Furthermore, the effects of oxysterols or sterols are completely different to those of the sulfated ones, indicating that intracellular oxysterol or sterol sulfation represents a novel regulatory mechanism involved in many biological events.The liver plays a pivotal role in the maintenance of lipid homeostasis. AZD6244 Accumulation of lipids in liver tissues leads to nonalcoholic fatty liver diseases. The spectrum of NAFLD ranges from simple non-progressive steatosis to progressive nonalcoholic steatohepatitis that results in liver cirrhosis and hepatocellular carcinoma. The accumulation of triglycerides and associated lipids and the occurrence of liver inflammation in the hepatocytes are believed to be the major pathogenic factors for the development of the diseases. Lowering lipid levels is an important element of successful NAFLD therapy. However, there is no approved treatment for NAFLD currently. The discovery of the novel cholesterol metabolites, 25HC3S and 25HCDS, which decrease intracellular lipid levels, has laid the groundwork for the development of the better therapies.