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Hepatic Lipin 1ß Expression is Diminished in Insulin-Resistant Obese Subjects and is Reactivated by Marked Weight Loss

¹Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO

Correspondence: bfinck{at}im.wustl.edu

Objective:Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1 and ß) 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 ß was quantified in liver and adipose tissue of extremely obese (average BMI = 60.8 kg/m²) human subjects undergoing gastric bypass surgery (GBS). Secondly, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator-activated receptor coactivator 1 (PGC-1) under normal or hyperinsulinemic conditions.

Results:The expression of lipin 1ß in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the HOMA-IR, but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1ß 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 down-regulated the expression of lipin 1ß, PGC-1, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1ß or PGC-1 reversed the effect of hyperinsulinemia on the expression of their target genes.

Conclusions:These studies suggest that hepatic lipin 1ß and PGC-1 expression is down-regulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity.

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