Disease relevance of Lpin1

• We recently identified mutations in the lipin gene, Lpin1, as the cause of lipodystrophy in the fatty liver dystrophy (fld) mouse [1].
• Here we identify impaired adipocyte differentiation as the basis for lipodystrophy in lipin-deficient mice and demonstrate that lipin is required for normal induction of the adipogenic gene transcription program [1].
• We found that the reduced adiposity in chow fed fld mice and resistance to obesity in fld mice fed a high-fat diet is associated with reduced adipogenic gene expression [1].
• Mice carrying mutations in the fatty liver dystrophy (fld) gene have features of human lipodystrophy, a genetically heterogeneous group of disorders characterized by loss of body fat, fatty liver, hypertriglyceridemia and insulin resistance [2].
• Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation [3].

High impact information on Lpin1

• Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin [2].
• However, several such genes, including SREBP-1, SREBP-2, and Lpin1, are also expressed in the endoneurium [4].
• We find that Lpin1 null mutations lead to lipoatrophy of the epineurium, and to the dysregulation of a battery of genes required for the regulation of storage lipid metabolism in both the endoneurium and peri/epineurium [4].
• Lipin is the product of the gene that is mutated in fatty liver dystrophy (fld) mice [Peterfy, M., Phan, J., Xu, P. & Reue, K (2001) Nat. Genet. 27, 121-124], which exhibit several phenotypic abnormalities including hyperlipidemia, defects in adipocyte differentiation, impaired glucose tolerance, and slow growth [5].
• The results suggest that insulin and epinephrine control lipin primarily by changing localization rather than intrinsic PAP activity [6].

Chemical compound and disease context of Lpin1

• The fatty liver dystrophy (fld) mutation is manifested in abnormalities of lipid and glucose metabolism and peripheral neuropathy [7].
• An autosomal recessive mutation, termed fatty liver dystrophy (fld), can be identified in neonatal mice by their enlarged and fatty liver (Sweet, H. O., Birkenmeier, E. H., and Davisson, M. T. (1988) Mouse News Letter 81, 69) [8].
• These findings indicate that altered expression of proteins involved in fatty acid oxidation is associated with triglyceride accumulation in the fld fatty liver [9].

Biological context of Lpin1

• This paradox was resolved by examining gene expression at 10-h intervals during 3T3-L1 cell differentiation, leading to detection of transient lipin expression at 10 h into the differentiation program, prior to the induction of PPARgamma and C/EBPalpha [1].
• Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro [1].
• Here we briefly describe the phenotypes and genetics of several mutants with blood and tissue lipid abnormalities, and then provide a more in-depth discussion of two mutations, fatty liver dystrophy (fld) and combined lipase deficiency (cld) [10].
• Genetic, physical, and transcript map of the fld region on mouse chromosome 12 [7].
• The results localize fld to the 0.42-cM interval between the microsatellite markers D12Mit170 and D12Mit184 [7].

Anatomical context of Lpin1

• Thus, we conclude that lipin expression is required prior to PPARgamma during adipocyte differentiation [1].
• Consistent with a requirement for lipin expression upstream of PPARgamma, differentiation of lipin-deficient mouse embryonic fibroblasts could be rescued by ectopic expression of PPARgamma [1].
• Mutations in the Lpin1 gene (encoding lipin) cause the lipodystrophy (adipose tissue deficiency) of the fld mouse, but the underlying mechanism has been unclear [11].
• These data suggest that the fld mutation is associated with an abnormality of myelin formation (dysmyelination) as well as demyelination and axonal degeneration that persists despite apparent resolution of the neonatal hypertriglyceridemia and associated lipase abnormalities [3].
• Furthermore, two axon-specific proteins, neurofilament 68K and growth-associated 43 protein, display altered expression in adult fld/fld sciatic nerves [3].

Associations of Lpin1 with chemical compounds

• Significant reductions of mRNAs for major adipocyte regulatory factors, including peroxisome proliferator activated receptor-gamma, sterol regulatory binding protein 1, CAAT/enhancer binding protein-alpha, and lipin 1 were correlated with the reduced transcript levels for key metabolic pathways in the WAT [12].
• The circadian expression of Lpin1, FKBP51 and S-adenosyl methionine decarboxylase was also abolished in the ADX mice [13].
• Serum and hepatic triglyceride levels were elevated 5-fold in suckling fld/fld mice compared to their +/? littermates but abruptly resolved at the suckling/weaning transition [8].
• Using a combination of indirect calorimetry and stable-isotope flux phenotyping, we determined that fld mice exhibit abnormal fuel utilization throughout the diurnal cycle, with increased glucose oxidation near the end of the fasting period and increased fatty acid oxidation during the feeding period [14].
• In contrast, epinephrine and oleic acid promoted dephosphorylation of lipin [6].

Regulatory relationships of Lpin1

• Thus, variations in lipin levels alone are sufficient to induce extreme states of adiposity and may represent a mechanism by which adipose tissue and skeletal muscle modulate fat mass and energy balance [15].

Other interactions of Lpin1

• The fld mutation maps near to but distinct from the Apob locus on mouse chromosome 12 [16].
• Acads gene deletion in BALB/cByJ mouse strain occurred after 1981 and is not present in BALB/cByJ-fld mutant mice [17].

Analytical, diagnostic and therapeutic context of Lpin1

• High performance thin-layer chromatography revealed deficiencies in phospholipids, glycosphingolipids, and some neutral lipids in fld/fld sciatic nerves harvested during the first several months of life (compared to their +/? littermates) [3].
• To better characterize the biochemical basis for the development of fatty liver in fld mice, we compared protein expression patterns in the fatty liver of fld mice and in the liver of phenotypically normal (wild-type) littermates using quantitative two-dimensional gel electrophoresis [9].
• After treatment of the impaired glucose-tolerant subjects with insulin sensitizers for 10 weeks, pioglitazone (but not metformin) resulted in a 60% increase in the insulin sensitivity index (S(i)) and a 32% decrease in IMCLs (both P < 0.01), along with an increase in lipin-beta (but not lipin-alpha) expression by 200% (P < 0.005) [18].

References