Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A₂and diet‐induced obesity

Abstract

Decrease in fat catabolic rate on consuming a high-fat diet contributes to diet-induced obesity. This study used group 1B phospholipase A(2) (Pla2g1b)-deficient mice, which are resistant to hyperglycemia, to test the hypothesis that Pla2g1b and its lipolytic product lysophospholipid suppress hepatic fat utilization and energy metabolism in promoting diet-induced obesity. The metabolic consequences of hypercaloric diet, including body weight gain, energy expenditure, and fatty acid oxidation, were compared between Pla2g1b(+/+) and Pla2g1b(-/-) mice. The Pla2g1b(-/-) mice displayed normal energy balance when fed chow, but were resistant to obesity when challenged with a hypercaloric diet. Obesity resistance in Pla2g1b(-/-) mice is due to their ability to maintain elevated energy expenditure and core body temperature when subjected to hypercaloric diet, which was not observed in Pla2g1b(+/+) mice. The Pla2g1b(-/-) mice also displayed increased postprandial hepatic fat utilization due to increased expression of peroxisome proliferator-activated receptor (PPAR)-alpha, PPAR-delta, PPAR-gamma, cd36/Fat, and Ucp2, which coincided with reduced postprandial plasma lysophospholipid levels. Lysophospholipids produced by Pla2g1b hydrolysis suppress hepatic fat utilization and down-regulate energy expenditure, thereby preventing metabolically beneficial adaptation to a high-fat diet exposure in promoting diet-induced obesity and type 2 diabetes.

Group 1B phospholipase A2 deficiency protects against diet-induced hyperlipidemia in mice

“…However, whereas the Pla2g1b +/+ mice showed progressive elevation from our laboratory have shown that Pla2g1b inactivation is protective against diet-induced obesity and hyperglycemia in mice ( 20,21 ), suggesting that Pla2g1b contributes directly to these diet-induced metabolic disorders. The Pla2g1b Ϫ / Ϫ mice are resistant to diet-induced obesity due to their ability to sustain elevated energy expenditure via increased hepatic fatty acid oxidation when fed a hypercaloric diet ( 22 ). The elevated fatty acid catabolic rate in the liver of Pla2g1b Ϫ / Ϫ mice also reduces dietary fat availability to other metabolically active tissues, thereby increasing their dependence on glucose as a fuel source and resulting in protection against diet-induced glucose intolerance and hyperglycemia ( 23 ).…”

“…mice can be abrogated with lysophosphatidylcholine (LPC) supplementation ( 22,23 ). Although the effects of hypercaloric diet and Pla2g1b inactivation upon glucose response and homeostasis had been examined, whether Pla2g1b inactivation also infl uences plasma lipid homeostasis in response to hypercaloric feeding has not been determined.…”

“…The mice were then given an intraperitoneal injection of Poloxamer 407 (P407) at a dosage of 1 g/kg body weight to inhibit lipolysis. For LPC supplementation studies, each mouse received 32 mg/kg of LPC, a dosage previously shown to restore LPC levels in Pla2g1b Ϫ / Ϫ mice to those observed in Pla2g1b +/+ mice ( 22,23 ), 1 h prior to P407 injection. Hourly blood samples were collected for plasma triglyceride measurements to determine hepatic VLDL production rates ( 27 ).…”

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

“…One of the major pathways for the formation of LPA is through the action of autotaxin on LysoPC ( 23 ). A major source of intestinal LysoPC is through the action of PLA2G1B (45)(46)(47)(48)(49)(50). PLA2G1B is a pancreatic PLA 2 that hydrolyzes fatty acids at the sn -2 position of phospholipids in the lumen of the small intestine.…”

“…PLA2G1B is a pancreatic PLA 2 that hydrolyzes fatty acids at the sn -2 position of phospholipids in the lumen of the small intestine. The uptake of LysoPC formed by the action of PLA2G1B was reported to be very effi cient and stimulated VLDL production ( 47 ). We hypothesized that LysoPC produced by the action of PLA2G1B on dietary unsaturated phospholipids might be a good substrate for the formation of unsaturated LPA in the enterocytes of the small intestine because i ) LysoPC is readily absorbed into the enterocytes of the small intestine ( 49 ), and ii ) autotaxin is highly expressed in the enterocytes of the small intestine ( 51 ).…”