UCLA

Lipins are a conserved family of phosphatidate phosphatase (PAP) enzymes that catalyze a critical step in glycerolipid biosynthesis, namely the removal of the phosphate group from phosphatidic acid to form diacylglycerol. While most lower organisms possess a single lipin gene, mammalian genomes contain genes for three lipin family members--lipin-1, lipin-2, and lipin-3--which presumably arose through gene duplication. Distinct tissue expression patterns, as well as unique disease phenotypes associated with different lipin deficiencies, suggest that each family member has a unique role in vivo. Lipin-1 deficiency causes lipodystrophy in the mouse, a consequence of its vital role in adipogenesis and triglyceride storage in adipose tissue. Lipin-2 deficiency affects lipid homeostasis in non-adipose tissues, including liver and brain, and causes a cyclical fever disease in humans called Majeed Syndrome. Little is known about the physiological function of lipin-3, expressed mainly in kidney, intestine, adipose tissue, and liver.

We are interested in teasing apart the unique physiological roles of each lipin family member. A simple working hypothesis is that each lipin is responsible for providing PAP activity in a unique but potentially overlapping set of tissues. In this dissertation, we expand on that model with the discovery of a complex system of cooperative relationships between lipin family members. We demonstrate that lipins work together to maintain lipid homeostasis in diverse tissues, from liver and brain (lipin-1 and lipin-2) to adipose tissue (lipin-1 and lipin-3) to intestine (lipin-2 and lipin-3). We also explore further the established roles of lipin-1 in adipogenesis and lipin-2 in Majeed Syndrome. Together, the findings in this dissertation build upon our previous model of lipin family function and demonstrate that the three mammalian lipins exist not only as separate enzymes specialized for distinct tissues. Instead, they should also be viewed as a cohesive family unit, responding to and functionally interacting with one another to achieve a common end of lipid homeostasis. The combination of individual and cooperative roles is customized for each tissue to create a sophisticated mammalian organism.