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Abnormalities in the Metabolism of Fatty Acids and Triacylglycerols in the Liver of the Goto-Kakizaki Rat: A Model for Non-Obese Type 2 Diabetes

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Lipids

Abstract

The Goto-Kakizaki (GK) rat is widely used as an animal model for spontaneous-onset type 2 diabetes without obesity; nevertheless, little information is available on the metabolism of fatty acids and triacylglycerols (TAG) in their livers. We investigated the mechanisms underlying the alterations in the metabolism of fatty acids and TAG in their livers, in comparison with Zucker (fa/fa) rats, which are obese and insulin resistant. Lipid profiles, the expression of genes for enzymes and proteins related to the metabolism of fatty acid and TAG, de novo synthesis of fatty acids and TAG in vivo, fatty acid synthase activity in vitro, fatty acid oxidation in liver slices, and very-low-density-lipoprotein (VLDL)-TAG secretion in vivo were estimated. Our results revealed that (1) the TAG accumulation was moderate, (2) the de novo fatty acid synthesis was increased by upregulation of fatty acid synthase in a post-transcriptional manner, (3) fatty acid oxidation was also augmented through the induction of carnitine palmitoyltransferase 1a, and (4) the secretion rate of VLDL-TAG remained unchanged in the livers of GK rats. These results suggest that, despite the fact that GK rats exhibit non-obese type 2 diabetes, the upregulation of de novo lipogenesis is largely compensated by the upregulation of fatty acid oxidation, resulting in only moderate increase in TAG accumulation in the liver.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

ACLY:

ATP-citrate lyase

ACOT1:

Acyl-CoA thioesterase 1

ACOX1:

Peroxisomal acyl-CoA oxidase 1

ACSL:

Long-chain acyl-CoA synthetase

APOC3:

Apolipoprotein CIII

CE:

Cholesteryl ester(s)

CPT1a:

Carnitine palmitoyltransferase 1a

CYP:

Cytochrome P450

DAG:

Diacylglycerol(s)

DGAT:

Diglyceride acyltransferase

ELOVL:

Fatty acid elongase

FABP1:

Fatty acid binding protein 1

FABPpm:

Plasma membrane-associated fatty acid binding protein

FAS:

Fatty acid synthase

FAT/CD36:

Fatty acid translocase

FATP:

Fatty acid transport protein

FFA:

Unesterified fatty acid(s)

GCK:

Glucokinase

GK rat:

Goto-Kakizaki rat

GPAT:

Glycerol-3-phosphate acyltransferase

G6Pase:

Glucose-6-phosphatase

G6PD:

Glucose-6-phosphate dehydrogenase

HNF4α:

Hepatic nuclear factor 4α

LCAD:

Long-chain acyl-CoA dehydrogenase

LPK:

L-type pyruvate kinase

LXRα:

Liver X receptor α

MCAD:

Medium-chain acyl-CoA dehydrogenase

MCD:

Malonyl-CoA decarboxylase

ME1:

Malic enzyme 1

MUFA:

Monounsaturated fatty acid(s)

P-ACC:

Phospho-acetyl-CoA carboxylase

PEPCK:

Phosphoenolpyruvate carboxykinase

PGC1α:

Peroxisome proliferator-activated receptor gamma coactivator 1α

PPAR:

Peroxisome proliferator-activated receptor

SCD:

Stearoyl-CoA desaturase

SREBP-1c:

Sterol regulatory element binding protein-1c

TAG:

Triacylglycerol(s)

T2D:

Type 2 diabetes

TLC:

Thin-layer chromatography

UCP2:

Uncoupling protein 2

VLCAD:

Very-long-chain acyl-CoA dehydrogenase

VLDL:

Very-low-density lipoprotein

WI rat:

Wistar rat, a control corresponding to the GK rat

ZF rat:

Obese Zucker (fa/fa) rat

ZL rat:

Lean Zucker (?/+) rat

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Acknowledgments

This work was partially supported by a Grant-in-Aid (22590120) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama, 350-0295, Japan

    Minako Karahashi, Yuko Hirata-Hanta, Kohei Kawabata, Daisuke Tsutsumi, Misaki Kametani, Nanako Takamatsu, Takeshi Sakamoto, Tohru Yamazaki, Yoichi Kawashima & Naomi Kudo

  2. Department of Pharmaceutical Sciences, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan

    Satoshi Asano

  3. Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba, 283-8555, Japan

    Atsushi Mitsumoto

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  1. Minako Karahashi
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  2. Yuko Hirata-Hanta
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Correspondence to Naomi Kudo.

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Karahashi, M., Hirata-Hanta, Y., Kawabata, K. et al. Abnormalities in the Metabolism of Fatty Acids and Triacylglycerols in the Liver of the Goto-Kakizaki Rat: A Model for Non-Obese Type 2 Diabetes. Lipids 51, 955–971 (2016). https://doi.org/10.1007/s11745-016-4171-8

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