Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification

Diraison, Frédérique; Beylot, M.

doi:10.1152/ajpendo.1998.274.2.e321

Cited by 75 publications

(77 citation statements)

References 32 publications

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“…In the present study, DNL might therefore explain part of the higher contribution of splanchnic sources to VLDL TGs in insulin-resistant compared with insulin-sensitive subjects. It has been proposed that the liver stores TGs to accommodate fatty acids that have accumulated in excess of requirement for oxidation and/or secretion as VLDL (36,37). In fact, after a 24-h fast, there is a fourfold increase in the neutral fat content of the mouse liver (38), although this is yet to be demonstrated in humans.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of Splanchnic Fat to VLDL Triglyceride Is Greater in Insulin-Resistant Than Insulin-Sensitive Men and Women

et al. 2007

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OBJECTIVE-We aimed to determine differences in the postprandial contributions of different fatty acid sources to VLDL triglycerides (TGs) in healthy men and women with varying degrees of insulin resistance.RESEARCH DESIGN AND METHODS-Insulin-resistant (n ϭ 11) and insulin-sensitive (n ϭ 11) men and women (n ϭ 6) were given an intravenous infusion of [ 2 H 2 ]palmitic acid to investigate systemic nonesterified fatty acid (NEFA) incorporation into VLDL TGs. Participants were also fed a mixed meal containing [U-13 C]palmitic acid to investigate the contribution of dietary fatty acids to VLDL TG production. Blood samples were taken over the following 6 h. Separation of VLDL was performed by density gradient ultracentrifugation and immunoaffinity techniques specific to apolipoprotein B-100. RESULTS-Insulin

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Section: Discussionmentioning

confidence: 99%

The Contribution of Splanchnic Fat to VLDL Triglyceride Is Greater in Insulin-Resistant Than Insulin-Sensitive Men and Women

et al. 2007

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“…Furthermore, protein levels of FAS and SCD were increased in livers of apoB/BATless mice. Lipogenesis is a modest but significant source of TG for VLDL secretion in rodents (33,43) and in humans with obesity and insulin resistance (44,45). Studies from the laboratory of Goldstein and Brown have characterized in detail the role of the basic/ helix-loop-helix/leucine zipper transcription factor, SREBP1c, in the regulation of hepatic lipogenesis (8).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Zhang

Hernandez‐Ono

Siri

et al. 2006

Journal of Biological Chemistry

142

108

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Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064 -46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPAR␥2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPAR␥, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPAR␥ antisense oligonucleotide resulted in dramatic reductions of both PPAR␥1 and PPAR␥2 mRNA, PPAR␥2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/ BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPAR␥2. The mechanism whereby hepatic Ppar␥2 gene expression is increased and how PPAR␥2 stimulates lipogenesis is under investigation.We reported previously that apoB/BATless mice, a model generated by crossing mice expressing human apolipoprotein B (apoB) 3 (1) with mice lacking brown adipose tissue (BATless) (2), have hypertriglyceridemia and hypercholesterolemia because of a 2-3-fold increase in the secretion of very low density lipoprotein (VLDL) apoB and triglycerides (TG) relative to mice expressing apoB only (3). Similar levels of apoB mRNA in the livers of apoB and apoB/BATless mice indicated that the differences in apoB secretion resulted from differences in posttranscriptional regulation of VLDL assembly and secretion (4). There were no differences in hepatic levels of microsomal triglyceride transfer protein mRNA (3), a critical factor in the early co-and post-translational regulation of apoB-containing lipoprotein secretion (5). Low density lipoprotein receptor mRNA levels in liver were higher in apoB/BATless compared with apoB mice (3), indicating that increased apoB secretion in apoB/BATless mice did not result from reduced interactions of the low density lipoprotein receptor with nascent apoB lipoproteins (6).Associated with a rising prevalence of obesity and insuli...

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“…In particular, the role of plasma albumin-bound FA as a direct stimulus of the assembly and secretion of apoB-lipoproteins has remained controversial despite numerous investigations. In vivo studies in humans support an important role of plasma FA delivery to the liver as a stimulus for apoB and TG secretion (29,30,33,(51)(52)(53), but none of those studies directly tested the effect of increasing FA delivery to the liver. Lewis et al (24) report increased apoB secretion as a consequence of infusing Intralipid and heparin to raise FA levels, but Malmstrom et al (26) were unable to show increased apoB secretion after raising plasma FA levels with heparin alone.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Hepatic Apolipoprotein B-lipoprotein Assembly and Secretion by the Availability of Fatty Acids

Zhang

Hernandez‐Ono

et al. 2004

Journal of Biological Chemistry

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The in vivo effects of increased delivery of fatty acids (FA) to the liver are poorly defined. Therefore, we compared the effects of infusing either 6 mM oleic acid (OA) bound to albumin, 0.5-20% Intralipid, or saline for 3 or 6 h into male C57BL/6J mice. Infusions were followed by studies of triglyceride (TG) and apoB secretion. Although plasma FA levels increased similarly after either 20% Intralipid or 6 mM OA, TG secretion increased only after infusion of 4 -20% Intralipid; TG secretion was unchanged by 6 mM OA. By contrast, 6-h infusions of either 6 mM OA or 4 -20% Intralipid increased apoB secretion. 6 mM OA and 20% Intralipid each increased secretion of apoB from primary hepatocytes ex vivo. Importantly, 0.5-2% Intralipid, which delivered more FA to the liver than 6 mM OA, did not stimulate apoB secretion. Hepatic apoB mRNA levels were unaffected by either 6 mM OA or 20% Intralipid, but microsomal triglyceride transfer protein mRNA was significantly lower after 6-h infusions with 6 mM OA versus either saline or 20% Intralipid. Lower microsomal triglyceride transfer protein mRNA levels were associated with reduced hepatic TG mass after 6-h infusions of 6 mM OA. We conclude that 1) increased FA delivery to the liver in vivo increases secretion of apoBlipoproteins via post-transcriptional mechanisms, 2) OA-induced apoB-lipoprotein secretion occurred at least in part via mechanisms other than by providing substrate for TG synthesis, and 3) the route of delivery of FA is important for its effects on apoB secretion.Regulation of the assembly and secretion of apolipoprotein B (apoB)-lipoproteins and, in particular, very low density lipoprotein (VLDL), 1 by the liver has been studied intensively for many years in cultured hepatocytes (1-4). Many laboratories have also conducted in vivo studies of apoB-lipoprotein secretion in humans and animal models (5-7). However, despite the presence of a large body of work, several questions remain incompletely answered.First and foremost is the question of whether increased flux of plasma fatty acids (FA) to the liver can stimulate VLDL secretion. Studies in cultured liver cell lines, primary hepatocytes, and perfused livers have provided conflicting results relative to the role of FA delivery in VLDL secretion. Thus, several (8 -13), but not all (14 -16) studies in cultured liver cell lines support the proposal that apoB secretion is increased by increased FA uptake. Studies in primary hepatocytes from fed rats (16 -18) or hamsters (19,20) have failed to show that exogenous FA stimulate secretion of apoB. However, we were able recently to demonstrate oleic acid (OA)-induced apoB secretion in primary hepatocytes from fasted mice (21). Results from perfused rat livers have also been mixed; OA had no effect on apoB secretion in chow-fed rats (22) but increased apoB secretion in fasted (22) or high carbohydrate diet-fed (23) rats. In vivo studies in humans have also been inconclusive. Lewis et al. (24,25) demonstrate that, when they increased the plasma levels of FA by infusin...

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Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification

Cited by 75 publications

References 32 publications

The Contribution of Splanchnic Fat to VLDL Triglyceride Is Greater in Insulin-Resistant Than Insulin-Sensitive Men and Women

The Contribution of Splanchnic Fat to VLDL Triglyceride Is Greater in Insulin-Resistant Than Insulin-Sensitive Men and Women

Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Regulation of Hepatic Apolipoprotein B-lipoprotein Assembly and Secretion by the Availability of Fatty Acids

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