Up‐regulation of hepatic lipolysis stimulated lipoprotein receptor by leptin: a potential lever for controlling lipid clearance during the postprandial phase

Abstract

As a hepatic receptor for triglyceride-rich lipoproteins, the lipolysis-stimulated lipoprotein receptor (LSR) may be involved in the dynamics of lipid distribution between the liver and peripheral tissues. Here, we explore the potential role of leptin in regulating LSR. At physiological concentrations (1-10 ng/ml), leptin increased LSR protein and mRNA levels in Hepa1-6 cells through an ERK1/2-dependent and α-amanitin-sensitive pathway. In vivo, leptin treatment of C57BL6/Rj mice (1 μg 2×/d, 8 d) led to a significant increase in hepatic LSR mRNA and protein, decreased liver triglycerides and increased VLDL secretion as compared to controls. LSR(+/-) mice with elevated postprandial lipemia placed on a high-fat (60% kcal) diet exhibited accelerated weight gain and increased fat mass as compared to controls. While plasma leptin levels were increased 3-fold, hepatic leptin receptor protein levels and phosphorylation of ERK1/2 were significantly reduced. Therefore, leptin is an important regulator of LSR protein levels providing the means for the control of hepatic uptake of lipids during the postprandial phase. However, this may no longer be functional in LSR(+/-) mice placed under a chronic dietary fat load, suggesting that this animal model could be useful for the study of molecular mechanisms involved in peripheral leptin resistance.

A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice

“…Because altered lipase activity can affect triglyceride clearance and leptin may act on the liver to promote postprandial triglyceride clearance, 25 we performed an oral lipid tolerance test on mice with a loss of leptin signaling in the liver. These mice had no alterations in lipid tolerance compared with controls (Supporting Fig.…”

Structure and Function of the Lipolysis Stimulated Lipoprotein Receptor

“…Continued monitoring of LSR +/-mice on standard laboratory chow diet revealed significant weight gain and increased leptin with age as compared to control mice (Stenger et al, 2010). This was most marked in female LSR +/-mice, where body mass was increased 1.5 fold due to increased body fat mass, accompanied by a disproportionate 3-fold increase in plasma leptin, a satiety hormone produced by the adipose tissue.…”

“…The distention of the stomach following a meal can lead to increased leptin secretion by adipocytes, thus controlling appetite and energy storage, consistent with its effect as a satiety factor. It was recently demonstrated that leptin can regulate postprandial lipemia by increasing hepatic LSR protein levels (Stenger et al, 2010). Indeed, physiological concentrations of leptin (1 to 10 ng/mL) significantly and rapidly (within 1 h), increased LSR protein levels in vitro in Hepa1-6 cells.…”

“…Thus, during the postprandial phase, leptin directly affects dietary lipid metabolism and storage through its action on LSR at the liver. This mechanism represents a lever for the regulation of dietary lipid uptake, degradation and distribution, thus contributing to maintaining an appropriate lipid homeostasis (Stenger et al, 2010) (Figure 5A). Under normal conditions, physiological levels of leptin are sufficient to maintain an optimal amount of LSR at the cell surface, permitting clearance of TG-rich lipoproteins during the postprandial phase.…”

“…Under normal conditions, physiological levels of leptin are sufficient to maintain an optimal amount of LSR at the cell surface, permitting clearance of TG-rich lipoproteins during the postprandial phase. However, when leptin interaction with its receptor in the liver is impaired, such as in leptin resistance often observed in obesity, LSR protein levels at the cell surface may no longer be optimal, leading to decreased efficiency in removing lipids from the cell surface, resulting in elevated postprandial lipemia (Stenger et al, 2010, reproduced with permission from Faseb J).…”