Caenorhabditis elegans Perilipin Is Implicated in Cold-Induced Lipolysis and Inhibits Autophagy in Early Embryos.

Animals use neutral lipids, particularly triacylglycerols (TAGs), to store energy. TAGs are universally organized into dynamic cytoplasmic structures called lipid droplets (LDs). In mammals TAG breakdown is catalysed by lipases, such as hormonesensitive lipase (HSL). LD membrane-resident proteins called perilipins (PLINs) regulate some of these lipases. The model organism Caenorhabditis elegans has a single known PLIN homologue and orthologues of most lipases including HSL. HOSL-1 (the HSL orthologue in C. elegans) is responsible for production of cryoprotective glycerol in cold conditions, in addition to its role in fasting-induced lipolysis. We employed this model of cold exposure to study the role of PLIN-1 in the regulation of HOSL-1. Our results suggest that both HOSL-1 and PLIN-1 are required for cold tolerance and for lipid breakdown in cold. However, the loss of PLIN-1 partially rescued the phenotype of hosl-1 null mutants exposed to cold, suggesting the presence of an alternative pathway generating glycerol via lipolysis. In early embryos, PLIN-1 knock-out results in accumulation of lipids and formation of cytoplasmic clusters of autophagic marker LGG-1, supporting the role of autophagy as an alternative lipolytic pathway in C. elegans, as is the case in mammals.

Novel Mutation (T273R) in Thyroid Hormone Receptor ß Gene Provides Further Insight into Cryptic Negative Regulation by Thyroid Hormone.

Production of thyroid hormone is precisely regulated in a negative feed-back mechanism that depends critically on thyroid hormone receptor ß (TRß). This mechanism decreases production of thyrotropin- releasing hormone (TRH) and thyrotropin (TSH) in the hypothalamus and pituitary gland in response to high levels of circulating thyroid hormones (TH). Despite the wealth of accumulated knowledge, it is still not clear how exactly this negative regulation is executed. The syndrome of resistance to thyroid hormone (RTH), in which the levels of TH are not properly sensed, represents naturally occurring situations in which molecular components of this regulation are displayed and may be uncovered. TRß, which is central to this regulation, is in the majority of RTH cases mutated in a way that preserves some functions of the receptor. Approximately 150 different mutations in TRß have been identified to date. Here, we hypothesized that additional pathogenic mutations in TRß are likely to exist in human population and analysed clinical cases with suspected RTH. In keeping with our prediction, analysis of 17 patients from nine families led to identification of four presumed pathogenic mutations of TRß, including a previously unknown mutation, T273R. This suggests that threonine 273 is likely to be critical for the normal function of TRß, possibly due to its role in helix 12 mobility and interaction with coactivators, and thus supports the concept that TRß-dependent trans-activating function is necessary for the inhibition of TRH and TSH expression in response to elevated levels of TH.