UCLA

Members of the lipin protein family -- lipin-1, lipin-2 and lipin-3 -- catalyze the penultimate step in triacylglycerol (TAG) synthesis, the dephosphorylation of phosphatidic acid (PA) to form diacylglycerol. The founding member of the family, lipin-1, has been studied most extensively and has been implicated in metabolic diseases that include lipodystrophy, obesity and insulin resistance. The three lipin proteins exhibit distinct tissue distributions and therefore likely have unique physiological roles, which at present are not well understood. The focus of this dissertation has been to augment our understanding of the physiological and molecular roles of lipin family members through the use of various genetic and molecular tools. We generated lipin-2-deficient mice and determined that loss of lipin-2 causes hepatic and neurological defects in mice. These symptoms were associated with impaired TAG homeostasis in liver, and the accumulation of the lipin enzyme substrate, PA, in cerebellum. Interestingly, in both tissues, we uncovered relationships between lipin-1 and lipin-2 activities, which were particularly important in maintaining hepatic lipid homeostasis under conditions of metabolic stress such as a high fat diet, and in cerebellar function during aging. In addition to the functional interactions between lipin-1 and lipin-2, we determined that the two proteins interact in a protein complex in liver. Furthermore, lipin-1 and lipin-2 influence the protein levels of one another, and this requires a sequence motif in lipin-1 that has been shown to promote nuclear localization and PA binding. Analysis of lipin-2 KO mice also led to the discovery of a role for lipin proteins in bone homeostasis, with lipin-2 deficiency causing altered trabecular bone architecture, which was exacerbated on a high fat diet. Finally, an initial characterization of lipin-3 deficiency in mice is presented. Overall, these studies show that lipin protein family members cooperate to maintain normal glycerolipid homeostasis in vivo. The further elucidation of the regulation and function of lipin protein interactions will contribute to our understanding of lipid homeostasis in normal and diseased states.