Mice Lacking Phosphatidylinositol Transfer Protein-α Exhibit Spinocerebellar Degeneration, Intestinal and Hepatic Steatosis, and Hypoglycemia

Abstract

Phosphatidylinositol transfer proteins (PITPs) regulate the interface between lipid metabolism and cellular functions. We now report that ablation of PITP␣ function leads to aponecrotic spinocerebellar disease, hypoglycemia, and intestinal and hepatic steatosis in mice. The data indicate that hypoglycemia is in part associated with reduced proglucagon gene expression and glycogenolysis that result from pancreatic islet cell defects. The intestinal and hepatic steatosis results from the intracellular accumulation of neutral lipid and free fatty acid mass in these organs and suggests defective trafficking of triglycerides and diacylglycerols from the endoplasmic reticulum. We propose that deranged intestinal and hepatic lipid metabolism and defective proglucagon gene expression contribute to hypoglycemia in PITP␣ ؊/؊ mice, and that hypoglycemia is a significant contributing factor in the onset of spinocerebellar disease. Taken together, the data suggest an unanticipated role for PITP␣ in with glucose homeostasis and in mammalian endoplasmic reticulum functions that interface with transport of specific luminal lipid cargoes. PITPs1 mobilize PtdIns or PtdCho between membrane bilayers in vitro (1,2). In vivo studies demonstrate that PITPs control the interface between membrane trafficking and lipid metabolic pathways in yeast (3-6). By contrast, the physiological functions for mammalian PITPs, which are structurally unrelated to yeast PITPs (7, 8), are not understood at either the cellular or organismal levels.Mammals express at least three soluble PITPs: PITP␣, PITP␤, and rdgB␤ (9 -11). PITP␣ and PITP␤ share 77% primary sequence identity, are encoded by distinct genes, and exhibit biochemical differences. Yet both PITP␣ and PITP␤ (and even yeast PITPs) function as soluble factors that stimulate various reconstitutions of PIP-dependent functions in permeabilized mammalian cells. These functions include regulated and constitutive membrane trafficking and phospholipase Cdependent signaling through G-protein-coupled receptors (12)(13)(14). Given the lack of PITP specificity in these assays, it remains unclear how faithful such reconstitutions are in reporting physiological functions for mammalian PITPs. Genetic studies are providing initial clues regarding PITP function in metazoans. An inherited form of light-enhanced retinal degeneration in Drosophila results from inactivation of a membrane-bound PITP (15). In mice, reduction of PITP␣ to 18% of wild-type levels is the basis for the vibrator neurodegenerative disorder (16,26). Gene ablation approaches suggest PITP␤ plays an essential housekeeping function, whereas PITP␣ is nonessential for ES cell viability and is not a quantitatively significant factor in membrane trafficking, PIP metabolism, or growth factor signaling in ES cells (17).In this report, we describe the consequences associated with ablation of PITP␣ function in the mouse. We find that PITP␣, although dispensable for prenatal development, is required for neonatal survival. PITP␣ Ϫ/Ϫ neonates suffer from a...

Membrane lipids and vesicular traffic

“…In yeast, membrane flux through the exocytic pathway is regulated by cytosolic Sec14 [28], a family of cytosolic phosphatidylcholine/phosphatidylinositol transfer proteins that via their dual specificity may act as sensors of lipid composition and adapt lipid metabolism. Whereas one mammalian phosphatidylinositol transfer protein, PITPa, may have a related function and reports back to the nucleus [29], the highly homologous Golgi-associated PITPb is essential for growth [30]. PITPb binds sphingomyelin, which is unexpected as this lipid is thought to be confined to the Golgi lumen.…”

“…Based on the prediction that the active center would be similar to that of the lipid phosphate phosphatase (LPP) family, the authors employ a functional cloning strategy in yeast to identify two mammalian sphingomyelin synthases, SMS1 in the Golgi and SMS2 at the plasma membrane, where it is presumably active in ceramide/diacylglycerol-mediated signaling events. [28][29][30]. This paper unravels the mechanism by which the ceramide transfer protein CERT specifically transports ceramide from the ER to the site of Golgi sphingomyelin synthesis [16 ].…”

Phosphatidylinositol Transfer Protein Expression Altered by Aging and Parkinson Disease

“…It seems that the decrease of PI-TP protein level may be one of the important factors that lead to disturbing of phospholipids signaling and also may be involved in neurodegeneration of CNS. Alb et al (2002Alb et al ( , 2003 indicated that lack of PI-TPα caused aponecrotic spinocerebrallar disease in PI-TPα knockout mice. The mice lacking PI-TPα die soon after birth (Alb et al, 2002).…”

Phosphatidylinositol transfer proteins: From closed for transport to open for exchange

“…In line with being highly conserved in evolution both isomers are essential in cell function. So it was shown that murine embryonic stem (ES) cells deficient in PI-TPa developed normally during embryogenesis, yet the pups died early after birth stemming from complicated organ failure (Alb et al, 2003). On the other hand, PI-TPb gene ablation failed to give viable ES cells (Alb et al, 2002).…”