The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD + -dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in dietinduced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBPdependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis. Lipids and sterols play key roles in diverse biological processes in eukaryotes, such as membrane biosynthesis, intra-and extracellular signaling, and energy storage. In humans, aberrant lipid and cholesterol homeostasis has been linked to a number of diseases prevalent in the developed world, including metabolic syndrome-a constellation of conditions and diseases that includes obesity, insulin resistance, liver steatosis, and hypertension, as well as type 2 diabetes, cardiovascular disease, and cancers (Cornier et al. 2008). An improved understanding of the molecular mechanisms governing lipid/cholesterol homeostasis might lead to novel therapeutic strategies to ameliorate such diseases.Fasting (short-term food deprivation) produces a rapid metabolic shift from lipid/cholesterol synthesis and fat storage to mobilization of fat, and recent studies have suggested that fasting may improve conditions associated with metabolic syndrome (Varady and Hellerstein 2008;Fontana et al. 2010). There is thus keen interest in determining the mechanism of fasting-dependent regulation of lipid/cholesterol metabolism to facilitate the development

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

Histone 3 lysine 9 tri‐methylation (H3K9me3) is a hallmark of heterochromatin, a repressive structure found at repetitive and telomeric regions in the genome. This histone modification plays a critical role in the temporal control of heterochromatic replication and the regulation of euchromatic gene expression. Alterations in H3K9me3 and heterochromatin are directly associated with the onset of genomic instability and cancer. The lack of H3K9me3 has also been shown to be a contributor to the premature aging disease Hutchinson‐Gilford Progeria Syndrome. These few examples highlight an important link between the levels of H3K9me3, cancer, and premature aging. Identifying factors that influence H3K9me3 and heterochromatin dynamics will have profound implications in pathophysiology. We recently identified the first histone lysine‐specific tri‐demethylase family (JMJD2A‐D) in human and C. elegans (JMJD‐2) that regulate H3K9me3 and H3K36me3 levels. We uncovered a novel and highly conserved role for the JMJD2 proteins in multiple DNA‐templated processes. We have also demonstrated that the phenotypes are a reflection of altered chromatin structure. Our observations suggest that JMJD2 proteins are important regulators of the chromatin state from worm to human. We will present these findings as well as our most recent advances into understanding the molecular basis of the JMJD‐2‐related phenotypes.