Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice

Kaori Minehira (Corresponding Author), Stephen G. Young, Claudio J. Villanueva, Laxman Yetukuri, Matej Oresic, Mark K. Hellerstein, Robert V. Farese Jr., Jay D. Horton, Frederic Preitner, Bernard Thorens, Luc Tappy

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Abstract

The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity.
Original languageEnglish
Pages (from-to)2038-2044
Number of pages7
JournalJournal of Lipid Research
Volume49
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

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Insulin Resistance
Triglycerides
Insulin
Lipids
Liver
Muscle
Adiposity
Tissue
Plasmas
Muscles
Adipose Tissue
Skeletal Muscle
Apolipoprotein B-100
Glucose
Ideal Body Weight
Glucose Clamp Technique
Ceramides
Diglycerides
Clamping devices
Fatty Liver

Keywords

  • Microsomal triglyceride transfer protein
  • triglyceride-rich lipoprotein
  • fatty liver
  • insulin resistance
  • obesity
  • de novo lipogenesis

Cite this

Minehira, K., Young, S. G., Villanueva, C. J., Yetukuri, L., Oresic, M., Hellerstein, M. K., ... Tappy, L. (2008). Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. Journal of Lipid Research, 49, 2038-2044. https://doi.org/10.1194/jlr.M800248-JLR200
Minehira, Kaori ; Young, Stephen G. ; Villanueva, Claudio J. ; Yetukuri, Laxman ; Oresic, Matej ; Hellerstein, Mark K. ; Farese Jr., Robert V. ; Horton, Jay D. ; Preitner, Frederic ; Thorens, Bernard ; Tappy, Luc. / Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. In: Journal of Lipid Research. 2008 ; Vol. 49. pp. 2038-2044.
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title = "Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice",
abstract = "The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity.",
keywords = "Microsomal triglyceride transfer protein, triglyceride-rich lipoprotein, fatty liver, insulin resistance, obesity, de novo lipogenesis",
author = "Kaori Minehira and Young, {Stephen G.} and Villanueva, {Claudio J.} and Laxman Yetukuri and Matej Oresic and Hellerstein, {Mark K.} and {Farese Jr.}, {Robert V.} and Horton, {Jay D.} and Frederic Preitner and Bernard Thorens and Luc Tappy",
year = "2008",
doi = "10.1194/jlr.M800248-JLR200",
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Minehira, K, Young, SG, Villanueva, CJ, Yetukuri, L, Oresic, M, Hellerstein, MK, Farese Jr., RV, Horton, JD, Preitner, F, Thorens, B & Tappy, L 2008, 'Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice', Journal of Lipid Research, vol. 49, pp. 2038-2044. https://doi.org/10.1194/jlr.M800248-JLR200

Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. / Minehira, Kaori (Corresponding Author); Young, Stephen G.; Villanueva, Claudio J.; Yetukuri, Laxman; Oresic, Matej; Hellerstein, Mark K.; Farese Jr., Robert V.; Horton, Jay D.; Preitner, Frederic; Thorens, Bernard; Tappy, Luc.

In: Journal of Lipid Research, Vol. 49, 2008, p. 2038-2044.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice

AU - Minehira, Kaori

AU - Young, Stephen G.

AU - Villanueva, Claudio J.

AU - Yetukuri, Laxman

AU - Oresic, Matej

AU - Hellerstein, Mark K.

AU - Farese Jr., Robert V.

AU - Horton, Jay D.

AU - Preitner, Frederic

AU - Thorens, Bernard

AU - Tappy, Luc

PY - 2008

Y1 - 2008

N2 - The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity.

AB - The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity.

KW - Microsomal triglyceride transfer protein

KW - triglyceride-rich lipoprotein

KW - fatty liver

KW - insulin resistance

KW - obesity

KW - de novo lipogenesis

U2 - 10.1194/jlr.M800248-JLR200

DO - 10.1194/jlr.M800248-JLR200

M3 - Article

VL - 49

SP - 2038

EP - 2044

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

ER -