Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism.

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as "OXPAT.

The peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) is a highly inducible transcriptional coactivator implicated in the coordinate regulation of genes encoding enzymes involved in hepatic fatty acid oxidation, oxidative phosphorylation, and gluconeogenesis. The present study sought to assess the effects of chronic PGC-1␣ deficiency on metabolic flux through the hepatic gluconeogenic, fatty acid oxidation, and tricarboxylic acid cycle pathways. To this end, hepatic metabolism was assessed in wild-type (WT) and PGC-1␣ ؊/؊ mice using isotopomer-based NMR with complementary gene expression analyses. Hepatic glucose production was diminished in PGC-1␣ ؊/؊ livers coincident with reduced gluconeogenic flux from phosphoenolpyruvate. Surprisingly, the expression of PGC-1␣ target genes involved in gluconeogenesis was unaltered in PGC-1␣ ؊/؊ compared with WT mice under fed and fasted conditions. Flux through tricarboxylic acid cycle and mitochondrial fatty acid ␤-oxidation pathways was also diminished in PGC-1␣ ؊/؊ livers. The expression of multiple genes encoding tricarboxylic acid cycle and oxidative phosphorylation enzymes was significantly depressed in PGC-1␣ ؊/؊ mice and was activated by PGC-1␣ overexpression in the livers of WT mice. Collectively, these findings suggest that chronic wholeanimal PGC-1␣ deficiency results in defects in hepatic glucose production that are secondary to diminished fatty acid ␤-oxidation and tricarboxylic acid cycle flux rather than abnormalities in gluconeogenic enzyme gene expression per se.Flux through hepatic gluconeogenesis, fatty acid oxidation (FAO), 3 tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation (OXPHOS) pathways can be modulated at multiple regulatory levels. Substrate availability, post-translational modification, and transcriptional regulation of genes encoding enzymes at various points can influence the capacity for, and the rate of flux through, each of these pathways. Moreover, flux through one pathway has an inevitable impact on the flux of the others. For instance, mitochondrial FAO is the principal source of energy in the hepatocyte, impacting the amount of chemical work that can be performed by the liver. Furthermore, the tricarboxylic acid cycle not only oxidizes acetyl-CoA generated by ␤-oxidation and produces reducing equivalents for ATP synthesis but also supplies carbons necessary for gluconeogenesis through pyruvate carboxylase (PC) and P-enolpyruvate carboxykinase (PEPCK). Thus, the tricarboxylic acid cycle is a critical hub linking FAO with gluconeogenesis and OXPHOS pathways.Recent work has shown that the peroxisome proliferatoractivated receptor ␥ (PPAR␥) coactivator-1␣ (PGC-1␣) is a highly inducible transcriptional coactivator that integrates multiple interconnected metabolic pathways in liver (1). PGC-1␣ controls transcription of genes involved in hepatic gluconeogenesis, fatty acid catabolism, oxidative phosphorylation (OXPHOS), and mitochondrial biogenesis (1-3). Although PGC-1␣ was originally identified ...

OBJECTIVE-Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1␣ and -␤) in liver and adipose tissue of obese subjects and to evaluate cellular mechanisms involved in the regulation of lipin 1 expression by physiologic stimuli. RESEARCH DESIGN AND METHODS-The expression of lipin 1␣ and -␤ was quantified in liver and adipose tissue of extremely obese (average BMI 60.8 kg/m 2 ) human subjects undergoing gastric bypass surgery (GBS). Second, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣ under normal or hyperinsulinemic conditions. RESULTS-The expression of lipin 1␤ in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the homeostasis model assessment of insulin resistance but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1␤ mRNA levels were strongly correlated with the expression of PGC-1␣, and overexpression of PGC-1␣ in HepG2 cells increased lipin 1 expression. Conversely, hyperinsulinemic culture conditions downregulated the expression of lipin 1␤, PGC-1␣, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1␤ or PGC-1␣ reversed the effect of hyperinsulinemia on the expression of their target genes.CONCLUSIONS-These studies suggest that hepatic lipin 1␤ and PGC-1␣ expression are downregulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity. Diabetes

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