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Molecular Mechanism of Age-Specific Hepatic Lipid Accumulation in PPARα (+/−):LDLR (+/−) Mice, an Obese Mouse Model

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Lipids

Abstract

This study aimed to clarify the molecular mechanisms of age-specific hepatic lipid accumulation accompanying hyperinsulinemia in a peroxisome proliferator-activated receptor α (PPARα) (+/−):low-density lipoprotein receptor (LDLR) (+/−) mouse line. The hepatic fat content, protein amounts, and mRNA levels of genes involved in hepatic lipid metabolism were analyzed in 25-, 50-, 75- and 100-week-old mice. Severe fatty liver was confirmed only in 50- and 75-week-old mice. The hepatic expression of proteins that function in lipid transport and catabolism did not differ among the groups. In contrast, the mRNA levels and protein amounts of lipogenic enzymes, including acetyl-coenzyme A carboxylase-1, fatty acid synthase, and glycerol-3-phosphate acyltransferase, enhanced in the mice with fatty liver. Elevated mRNA and protein levels of lipoprotein lipase and fatty acid translocase, which are involved in hepatic lipid uptake, were also detected in mice with fatty liver. Moreover, both protein and mRNA levels of sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor regulating lipid synthesis, had age-specific patterns similar to those of the proteins described above. Therefore, the age-specific fatty liver found in the PPARα (+/−):LDLR (+/−) mouse line is probably caused by age-specific expression of SREBP-1 and its downstream lipogenic genes, coordinated by the increased uptake of lipids. All of these factors might be affected by age-specific changes in serum insulin concentration.

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Abbreviations

ACC-1:

Acetyl-CoA carboxylase-1

ACO:

Acyl-CoA oxidase

CoA:

Coenzyme A

CT :

Cycle threshold

DBF:

Peroxisomal D-type bifunctional protein

FAS:

Fatty acid synthase

FAT:

Fatty acid translocase

FATP:

Fatty acid transport protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GPAT:

Glycerol-3-phosphate acyltransferase

HTGL:

Hepatic triglyceride lipase

LACS:

Long chain acyl-CoA synthase

LDLR:

Low-density lipoprotein receptor

L-FABP:

Liver fatty acid-binding protein

LPL:

Lipoprotein lipase

MCAD:

Medium chain acyl-CoA dehydrogenase

MTP:

Microsomal triglyceride transfer protein

PAGE:

Polyacrylamide gel electrophoresis

PCR:

Polymerase chain reaction

PPAR:

Peroxisome proliferator-activated receptor

PT:

Peroxisomal thiolase

SD:

Standard deviation

SDS:

Sodium dodecyl sulfate

SREBP-1:

Sterol regulatory element-binding protein-1

T1:

Short chain-specific 3-ketoacyl-CoA thiolase

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Authors and Affiliations

  1. Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan

    Yufeng Li, Eiko Sugiyama, Naoki Tanaka & Toshifumi Aoyama

  2. Department of Nutritional Science, Nagano Prefectural College, Nagano, 380-8525, Japan

    Eiko Sugiyama

  3. Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan

    Shin Yokoyama

  4. Department of Biochemistry, Hebei Medical University, 050017, Shijiazhuang, Hebei, China

    Lingling Jiang

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  1. Yufeng Li
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  2. Eiko Sugiyama
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  3. Shin Yokoyama
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  4. Lingling Jiang
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  5. Naoki Tanaka
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  6. Toshifumi Aoyama
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Correspondence to Eiko Sugiyama.

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Li, Y., Sugiyama, E., Yokoyama, S. et al. Molecular Mechanism of Age-Specific Hepatic Lipid Accumulation in PPARα (+/−):LDLR (+/−) Mice, an Obese Mouse Model. Lipids 43, 301–312 (2008). https://doi.org/10.1007/s11745-008-3161-x

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  • DOI: https://doi.org/10.1007/s11745-008-3161-x

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