SUMMARY LPIN1 encodes lipin-1, a phosphatidic acid phosphatase (PAP) enzyme that catalyzes the dephosphorylation of phosphatidic acid to form diacylglycerol. Homozygous LPIN1 gene mutations cause severe rhabdomyolysis, and heterozygous LPIN1 missense mutations may promote statin-induced myopathy. We demonstrate that lipin-1–related myopathy in the mouse is associated with a blockade in autophagic flux and accumulation of aberrant mitochondria. Lipin-1 PAP activity is required for maturation of autolysosomes, through its activation of the protein kinase D (PKD)-Vps34 phosphatidylinositol 3-kinase signaling cascade. Statin treatment also reduces PKD activation and autophagic flux, which are compounded by diminished mTOR abundance in lipin-1-haploinsufficent and –deficient muscle. Lipin-1 restoration in skeletal muscle prevents myonecrosis and statin toxicity in vivo, and activated protein kinase D rescues autophagic flux and lipid homeostasis in lipin-1–deficient cells. Our findings identify lipin-1 PAP activity as a component of the macroautophagy pathway, and define the basis for lipin-1–related myopathies.

Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg 2؉ -dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients.The mammalian lipin protein family is composed of three members, lipin-1, lipin-2, and lipin-3, each of which are ϳ100 kDa in size and have 44 -48% amino acid similarity (reviewed in Ref. 1). Orthologous lipin genes are present in plants, invertebrates, and single cell eukaryotes such as yeast and plasmodium (2), suggesting that lipin proteins play a fundamental cellular role that has been conserved in evolution. In particular, extended stretches of 100 -200 amino acids at the N-terminal and C-terminal regions of the protein (the N-LIP and C-LIP domains, respectively) are highly conserved among the three mammalian lipin family members and among species. Within the C-LIP domain are two key protein functional motifs as follows: a haloacid dehalogenase motif (DXDXT) found in a superfamily of Mg 2ϩ -dependent phosphatases (3, 4), and a transcription factor-binding motif (LXXIL) (5). These motifs confer two distinct molecular functions on members of the lipin family. All three mammalian lipins are Mg 2ϩ -dependent phosphatidate phosphatase (PAP) 4 enzymes, which catalyze the conversion of phosphatidate (PA) to diacylglycerol, a key step in the biosynthesis of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine (3, 4, 6, 7). Lipin-1 also acts as a transcriptional coact...

The prevalence of obesity in the western world has focused attention on factors that influence triglyceride biosynthesis, storage, and utilization. Members of the lipin protein family have a newly discovered enzymatic role in triglyceride and phospholipid biosynthesis as a phosphatidate phosphatase, and also act as an inducible transcriptional coactivator in conjunction with peroxisome proliferator-activated receptor c (PPARc) coactivator-1a and PPARa. Through these activities, the founding member of the family, lipin-1, influences lipid metabolism and glucose homeostasis in diverse tissues including adipose tissue, skeletal muscle, and liver. The physiological roles of lipin-2 and lipin-3 are less well defined, but are likely to carry out similar functions in glycerolipid biosynthesis and gene expression in a distinct tissue distribution.

Background: Lipins are phosphatidic acid phosphatases. In yeast, lipin is activated by the Nem1p-Spo7p complex. There is controversy as to whether a mammalian Spo7p ortholog exists. Results: The metazoan Spo7p ortholog is now identified and shown to interact with lipins in yeast, nematodes, and mammalian cells. Conclusion: NEP1-R1 is the metazoan Spo7p ortholog. Significance: The lipin activation system is conserved in evolution.

In addition to the hallmark neurological manifestations of Huntington's disease (HD), weight loss with metabolic dysfunction is often observed in the later stages of disease progression and is associated with poor prognosis. The mechanism for weight loss in HD is unknown. Using two mouse models of HD, the R6/2 transgenic and CAG140 knock-in mouse strains, we demonstrate that adipose tissue dysfunction is detectable at early ages and becomes more pronounced as the disease progresses. Adipocytes acquire a 'de-differentiated' phenotype characterized by impaired expression of fat storage genes. In addition, HD mice exhibit reduced levels of leptin and adiponectin, adipose tissue-derived hormones that regulate food intake and glucose metabolism. Importantly, some of these changes occur prior to weight loss and development of some of the characteristic neurological symptoms. We demonstrate that impaired gene expression and lipid accumulation in adipocytes can be recapitulated by expression of an inducible mutant huntingtin transgene in an adipocyte cell line and that mutant huntingtin inhibits transcriptional activity of the PGC-1alpha co-activator in adipocytes, which may contribute to aberrant gene expression. Thus, our findings indicate that mutant huntingtin has direct detrimental effects in cell types other than neurons. The results also indicate that circulating adipose-tissue-derived hormones may be accessible markers for HD prognosis and progression and suggest that adipose tissue may be a useful therapeutic target to improve standard of life for HD patients.