The sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that play a central role in cellular lipid homeostasis through the end-product feedback regulation of lipid synthesis. This feedback pathway is best understood in the case of cholesterol. Accumulation of cholesterol suppresses the proteolytic release of the transcriptionally active amino-terminal fragment of SREBP from the membrane-bound precursor. Experiments reported during the past year have led to a more complete understanding of the mechanisms that regulate the processing of SREBPs and their role in cellular lipid homeostasis. Regulation of lipid homeostasis is intimately associated with intracellular membrane trafficking; SREBPs undergo regulated transport from the endoplasmic reticulum to the Golgi apparatus in response to cellular lipid demand. The regulated step in this transport is the budding of a complex of SREBP and SREBP cleavage-activating protein into vesicles. In the present review we focus on recent results that give a more detailed picture of the mechanisms that are involved in end-product feedback regulation of lipid homeostasis.

No abstract

No abstract

Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.