Mice deficient small heterodimer partner (SHP) are protected from diet induced hepatic steatosis due to increased fatty acid oxidation and decreased lipogenesis. The decreased lipogenesis appears to be a direct consequence of very low expression of peroxisome proliferator activated receptor gamma 2 (PPARγ2), a potent lipogenic transcription factor, in the SHP−/− liver. The current study focuses on the identification of a SHP dependent regulatory cascade that controls PPARγ2 gene expression, thereby regulating hepatic fat accumulation. Illumina BeadChip array and real-time polymerase chain reaction were used to identify genes responsible for the linkage between SHP and PPARγ2 using hepatic RNAs isolated from SHP−/− and SHP-overexpressing mice. The initial efforts identify that hairy and enhancer of split 6 (Hes6), a novel transcriptional repressor, is an important mediator of the regulation of PPARγ2 transcription by SHP. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist ligand all-trans retinoic acid (atRA), and is repressed by SHP. Hes6 subsequently represses hepatocyte nuclear factor 4 alpha (HNF4α) activated-PPARγ2 gene expression via direct inhibition of the HNF4α transcriptional activity. Furthermore, we provide evidences that atRA treatment or adenovirus-mediated RARα overexpression significantly reduced hepatic fat accumulation in obese mouse models as observed in earlier studies and the beneficial effect is achieved via the proposed transcriptional cascade. Conclusions Our study describes a novel transcriptional regulatory cascade controlling hepatic lipid metabolism that identifies retinoic acid signaling as a new therapeutic approach to non-alcoholic fatty liver diseases.
This article is available online at http://www.jlr.org Supplementary key words hepatic steatosis •  -oxidation • oxygen consumption • respiratory quotient • insulin sensitivityA primary physiological function of the orphan nuclear receptor small heterodimer partner (SHP) is in the negative feedback regulation of Cyp7A1 gene expression in response to elevated bile acids ( 1, 2 ), although SHP independent bile acid feedback pathways have also been suggested ( 3-5 ). In addition, SHP plays a role in the basal bile fl ow rate through regulation of the bile salt export pump, BSEP ( 6 ).Interaction of SHP with hepatocyte nuclear factor alpha (HNF4 ␣ ), a gene responsible for maturity-onset diabetes of the young, suggested possible linkage between SHP and diabetes ( 7 ). Indeed, several heterozygous mutations in the SHP gene have been found in mildly obese Japanese subjects with maturity-onset diabetes of the young ( 8 ). Additional analysis revealed that the SHP mutations cosegregated with obesity but not with diabetes. Novel genetic variants were also found in UK and Danish populations, Abstract Mixed background SHP؊ / ؊ mice are resistant to diet-induced obesity due to increased energy expenditure caused by enhanced PGC-1 ␣ expression in brown adipocytes. However, congenic SHP ؊ / ؊ mice on the C57BL/6 background showed normal expression of PGC-1 ␣ and other genes involved in brown adipose tissue thermogenesis. Thus, we reinvestigated the impact of small heterodimer partner (SHP) deletion on diet-induced obesity and insulin resistance using congenic SHP ؊ / ؊ mice. Compared with their C57BL/6 wild-type counterparts, SHP ؊ / ؊ mice subjected to a 6 month challenge with a Western diet (WestD) were leaner but more glucose intolerant, showed hepatic insulin resistance despite decreased triglyceride accumulation and increased  -oxidation, exhibited alterations in peripheral tissue uptake of dietary lipids, maintained a higher respiratory quotient, which did not decrease even after WestD feeding, and displayed islet dysfunction. Hepatic mRNA expression analysis revealed that many genes expressed higher in SHP
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