Leptin inhibits apolipoprotein M transcription and secretion in human hepatoma cell line, HepG2 cells

Luo, Guanghua; Hurtig, Maria; Zhang, Xiaoying; Nilsson‐Ehle, Peter; Xu, N.

doi:10.1016/j.bbalip.2005.02.005

Cited by 35 publications

(21 citation statements)

References 22 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Leptin treatment of those mice restored apoM expression to levels similar to those in wild-type animals, which led Xu et al (19) to conclude that apoM is a direct target of leptin. Those data, however, conflict with results from the same group showing that apoM expression in HepG2 cells is decreased upon leptin treatment (37). Furthermore, recent other data indicate that insulin can regulate apoM expression in vitro (36), suggesting that the effects of leptin on apoM expression are mediated by insulin.…”

Section: Discussioncontrasting

confidence: 54%

Foxa2 Activity Increases Plasma High Density Lipoprotein Levels by Regulating Apolipoprotein M

Wolfrum

Howell

Ndungo

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Obesity, diabetes, insulin resistance, and hyperinsulinemia are frequently associated with a cluster of closely related lipid abnormalities such as low plasma levels of high density lipoprotein (HDL) and elevated levels of triglyceride, both known to increase the risk of developing atherosclerotic disease. The molecular mechanisms linking obesity, insulin resistance, and hyperinsulinemia to low HDL levels are incompletely understood. Here we demonstrate that insulin, through a Foxa2-mediated mechanism, inhibited the expression of apolipoprotein M (apoM), an important determinant of plasma pre-␤-HDL and ␣-HDL concentrations. Obese mice had decreased apoM expression and plasma pre-␤-HDL levels due to inactivation of Foxa2 in hyperinsulinemic states. Nuclear reexpression of Foxa2 with a phosphorylation-deficient mutant Foxa2T156A (Ad-T156A) activated apoM expression and increased plasma pre-␤-HDL and ␣-HDL levels. In contrast, haploinsufficient Foxa2 ؉/؊ mice exhibited decreased hepatic apoM expression and plasma pre-␤-HDL and HDL levels. The increase in plasma HDL levels and pre-␤-HDL formation by Foxa2 was mediated exclusively by apoM, as constitutive active expression of Foxa2 in apoM ؊/؊ mice had no effect on plasma HDL levels. Our results identify a fundamental mechanism by which insulin regulates plasma HDL levels in physiological and insulin-resistant states and thus have important implications for novel therapeutic approaches to prevent atherosclerosis. Epidemiological data indicate that a low level of high density lipoprotein (HDL)2 cholesterol is associated with increased cardiovascular morbidity and mortality (1, 2) and that genetic syndromes of high HDL are associated with longevity and decreased incidence of coronary heart disease (3). Furthermore, acute weight loss due to a hypocaloric diet frequently leads to a significant increase in plasma HDL concentrations in comparison with the base line, demonstrating that HDL metabolism is also under metabolic/hormonal control (4, 5).Mouse models of obesity and insulin resistance have been used extensively to study the molecular and genetic mechanisms of lipoprotein metabolism and atherosclerotic plaque formation. In general, HDL levels are inversely related to atherosclerosis susceptibility in humans and mice. The protective properties of HDL are most likely due to its role in reverse cholesterol transport but also may be related to the antioxidant and anti-inflammatory effects of HDL in the arterial wall (6). In humans, low HDL cholesterol levels may be associated with defects in synthesis and/or catabolism of the major HDL apolipoprotein, apoAI (7,8). The accelerated catabolism of HDL apolipoproteins is believed to reflect increased core lipid exchange between HDL and triglyceride-rich lipoproteins, leading to modifications of HDL composition and size that result in increased catabolism of HDL particles and reduced plasma HDL levels. HDL particles in hypertriglyceridemic subjects with obesity and insulin resistance are also frequently smaller and more susce...

show abstract

Section: Discussioncontrasting

confidence: 54%

Foxa2 Activity Increases Plasma High Density Lipoprotein Levels by Regulating Apolipoprotein M

Wolfrum

Howell

Ndungo

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Mechanistically, there are potential links between IGF-1 and HDL cholesterol through production and regulation of apolipoprotein M, a key component of pre-␤-HDL, a subclass of lipid-poor apolipoproteins that serves as a key acceptor of peripheral cellular cholesterol (18). Apolipoprotein M is in turn reported to be regulated by insulin, leptin, and IGF-1 (19,20). Alternatively, it has been speculated that HDL cholesterol variations in diabetic pregnancies are due to enhanced cholesteryl ester transfer protein activity, thereby establishing an adult lipid profile prematurely (21).…”

Section: Discussionmentioning

confidence: 99%

IGF-1 and Leptin Associate With Fetal HDL Cholesterol at Birth

Nelson

Freeman²,

Sattar³

et al. 2007

Diabetes

View full text Add to dashboard Cite

OBJECTIVE-Offspring of mothers with type 1 diabetes (OT1DM) demonstrate increased fat deposition, hyperinsulinemia, and hyperleptinemia in utero. We examined the influence of maternal diabetes on cord lipids at birth and relationship to body composition, cord insulin, leptin, and other hormonal measures. RESEARCH DESIGN AND METHODS-We performed an observational study measuring fetal, HDL, and LDL cholesterol; triglycerides; and nonesterified fatty acids (NEFAs) in a total of 139 OT1DM and 48 control subjects at birth and assessed cross-sectional relationships with birth weight, fetal insulin, leptin, adiponectin, and IGF-1. RESULTS-Concentrations of total cholesterol (male OT1DM[mean Ϯ SD] 1.49 Ϯ 0.45 mmol/l and male control subjects 1.74 Ϯ 0.33 mmol/l; P Ͻ 0.001), HDL cholesterol (0.53 Ϯ 0.21 and 0.74 Ϯ 0.19 mmol/l, respectively; P Ͻ 0.001), and NEFA (median 0.17 [interquartile range 2.30Ϫ2.95] and 0.21 [0.18 -0.36], respectively; P Ͻ 0.001) were significantly lower in male OT1DM, with no significant differences in female subjects. Differences in male subjects were independent of mode of delivery. Cord lipids were unrelated to birth weight in OT1DM and did not show consistent relationships with fetal insulin. Unexpectedly, IGF-1 was a strong correlate of HDL cholesterol in control subjects (r ϭ 0.40, P ϭ 0.002) and OT1DM (r ϭ 0.32, P Ͻ 0.001) but a negative correlate of triglycerides in control subjects (r ϭ Ϫ0.48, P Ͻ 0.001) and OT1DM (r ϭ Ϫ0.21, P ϭ 0.004), with these relationships present in both sexes. In OT1DM, leptin was also independently correlated (negatively, P Ͻ 0.001) with HDL cholesterol in male and female subjects.CONCLUSIONS-Maternal diabetes is associated with significant alterations in lipid levels in male fetuses. IGF-1, leptin, and male sex rather than insulin may be the major determinants of HDL cholesterol and triglycerides in utero. Diabetes 56:2705-2709, 2007 T here is increasing interest in how the intrauterine environment might influence cardiovascular and metabolic disease throughout life. In nondiabetic pregnancies, lower birth weight (1,2) (and smaller fetal abdominal circumference [3]) is associated with higher cord triglycerides and less consistently with lower HDL cholesterol (1,4) in addition to the welldescribed associations with increased risk of cardiovascular disease in adult life (5). Notably, much is still not known about the control or function of circulating fetal lipoproteins in utero. While free fatty acids cross the placenta, lipoproteins do not, and transfer of cholesterol is extremely limited (6). Oversupply of lipids, particularly nonesterified fatty acids (NEFAs), to the fetus have been proposed as a factor in promoting fetal adiposity (7,8). Maternal diabetes during pregnancy is associated with characteristic overgrowth of the fetus as well as marked hyperinsulinemia and hyperleptinemia, which is easily detectable in cord samples at birth (9). Offspring of mothers with type 2 diabetes are subject to in utero programming effects with increased risk of type 2 diabet...

show abstract

“…In the present study, we examined effects of LXR agonists on ABCA1 activation in relation to the regulation of apoM expression HepG2 cells. LightCycler real-time RT-PCR System was from Roche Applied Science (Mannheim,6 Germany). …”

mentioning

confidence: 99%

“…They elucidated the molecular mechanism by which apoM affects HDL particle size and to exploit a possible new pathway for therapeutic strategies aiming to reduce the development or progression of atherosclerosis [4]. ApoM mRNA levels could be regulated by many intracellular and extracellular factors, including platelet activating factor (PAF), insulin, leptin, transforming growth factor-beta (TGF-β), epidermal growth factor (EGF), hepatic growth factor (HGF), etc., although the function of apoM is unknown yet [5,6,7,8,9,10,11]. Further investigating the regulation of hepatic apoM expression may explore the pathophysiological functions of apoM in vivo.…”

mentioning

confidence: 99%

ABCA1 upregulating apolipoproein M expression mediates via the RXR/LXR pathway in HepG2 cells

Wang

Liu

et al. 2012

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

We have previously reported that liver X receptor (LXR) agonist, TO901317, could significantly inhibit hepatic apolipoprotein M (apoM) expression. It has been reported that TO901317 could activate the ATP-binding cassette transporter A1 (ABCA1) that mediates cholesterol efflux to the lipid-poor apoAI, which is an essential step for the high-density lipoprotein (HDL) formation. It is unknown if ABCA1 may regulate hepatic apoM expression. In the present study, HepG2 cells were cultured with the synthetic LXR agonists, TO901317 or GW3965 in the presence or absence of ABCA1 antagonist, disodium 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS). The mRNA levels of ABCA1, apoM and liver receptor homologue-1 (LRH-1) determined by the real-time RT-PCR. It demonstrated that both TO901317 and GW3965 could significantly enhance ABCA1 expression, and simultaneously, inhibit LRH1 expression. However, TO901317 alone could significantly inhibit apoM expression, while GW3965 alone did not influence apoM expression. ABCA1 antagonist, DIDS, have no effects on GW3965 induced upregulation of ABCA1 and downregulation of LRH1. However, apoM mRNA level was significantly decreased when the cells cultured with GW3965 together with DIDS. The present study demonstrated that apoM expression could be elevated by ABCA1 via the RXR/LXR pathway and LRH1 does not involve in the regulation of apoM by the activation of ABCA1, although the direct regulative pathway(s) between ABCA1 and apoM gene is still unknown yet.The detailed mechanism needs further investigation. 4Keywords: ATP-Binding cassette transporters; Apolipoprotein M; Liver Receptor Homolog-1; Liver X receptor Apolipoprotein M (apoM), one of the most recently discovered plasma apolipoproteins, is mainly associated with high density lipoproteins (HDL), with only a small proportion located in low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles [1]. Human apoM is exclusively expressed in the hepatocytes in liver and tubular epithelial cell in kidney, and small amounts were also found in fetal liver and fetal kidney [2]. Luo, et al.,[3] demonstrated that apoM could also be abundantly expressed in human colorectal tissues, although the pathophysiological importance of this expression and if it could influence plasma apoM pool are unknown. Wolfrum, et al., [4] demonstrated that apoM, by influencing preβ-HDL formation, being an important regulator of HDL metabolism in vivo, which could influence cholesterol efflux and the susceptibility of atherosclerosis. They elucidated the molecular mechanism by which apoM affects HDL particle size and to exploit a possible new pathway for therapeutic strategies aiming to reduce the development or progression of atherosclerosis [4]. ApoM mRNA levels could be regulated by many intracellular and extracellular factors, including platelet activating factor (PAF), insulin, leptin, transforming growth factor-beta (TGF-β), epidermal growth factor (EGF), hepatic growth factor (HGF), etc., although the function of apoM is un...

show abstract

Leptin inhibits apolipoprotein M transcription and secretion in human hepatoma cell line, HepG2 cells

Cited by 35 publications

References 22 publications

Foxa2 Activity Increases Plasma High Density Lipoprotein Levels by Regulating Apolipoprotein M

Foxa2 Activity Increases Plasma High Density Lipoprotein Levels by Regulating Apolipoprotein M

IGF-1 and Leptin Associate With Fetal HDL Cholesterol at Birth

ABCA1 upregulating apolipoproein M expression mediates via the RXR/LXR pathway in HepG2 cells

Contact Info

Product

Resources

About