Kobe J. Med. Sci., Vol. 54, No. 4, pp. E200–E208, 2008
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Role of Hepatic STAT3 in the Regulation of Lipid
SHINICHI KINOSHITA1, WATARU OGAWA1*, YASUO OKAMOTO1,
MOTOTSUGU TAKASHIMA1, HIROSHI INOUE1, 2,
YASUSHI MATSUKI3, EIJIRO WATANABE3, RYUJI HIRAMATSU3
and MASATO KASUGA1
1Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe
University Graduate School of Medicine, Kobe 650-0017, Japan;
2Present address: Frontier Science Organization, Kanazawa University, Kanazawa, 920-8641,
3Genomics Science Laboratories, Sumitomo Pharmaceuticals Co. Ltd., Takarazuka, Hyogo
Received 3 March 2008/ Accepted 12 March 2008
Key words: STAT3, Gluconeogenesis, Dyslipidemia, Diabetes mellitus
Regulation of hepatic gene expression is largely responsible for the control of
nutrient metabolism. We previously showed that the transcription factor STAT3
regulates glucose homeostasis by suppressing the expression of gluconeogenic genes in
the liver. However, the role of STAT3 in the control of lipid metabolism has remained
unknown. We have now investigated the effects of hepatic overexpression of STAT3,
achieved by adenovirus-mediated gene transfer, on glucose and lipid metabolism in
insulin-resistant diabetic mice. Forced expression of STAT3 reduced blood glucose and
plasma insulin concentrations as well as the hepatic abundance of mRNA for
phosphoenolpyruvate carboxykinase. However, it also increased the plasma levels of
triglyceride and total cholesterol without affecting those of low density lipoprotein– or
high density lipoprotein–cholesterol. The hepatic abundance of mRNAs for fatty acid
synthase and acetyl-CoA carboxylase, both of which catalyze the synthesis of fatty acids,
was increased by overexpression of STAT3, whereas that of mRNAs for sterol
regulatory element–binding proteins 1a, 1c, or 2 was unaffected. Moreover, the amount
of mRNA for acyl-CoA oxidase, which contributes to β-oxidation, was decreased by
forced expression of STAT3. These results indicate that forced activation of STAT3
signaling in the liver of insulin-resistant diabetic mice increased the circulating levels of
atherogenic lipids through changes in the hepatic expression of genes involved in lipid
metabolism. Furthermore, these alterations in hepatic gene expression likely occurred
through a mechanism independent of sterol regulatory element–binding proteins.
The liver plays a key role in the regulation of nutrient metabolism in living animals. Such
regulation is achieved by changes in the activity or abundance of enzymes that function in
glucose or lipid metabolism (11, 14). Various transcription factors participate in control of
the genes for such enzymes and thereby contribute to the regulation of nutrient metabolism.
For example, forkhead transcription factor O1 (FOXO1) and cAMP-responsive
element–binding protein are essential for induction of the genes for gluconeogenic enzymes
HEPATIC STAT3 AND LIPID METABOLISM
(8, 9, 13), whereas sterol regulatory element–binding proteins (SREBP1a, SREBP1c,
SREBP2) play a central role in regulation of the genes for various lipogenic enzymes (2, 16).
We recently showed that mice lacking signal transducer and activator of transcription 3
(STAT3) specifically in the liver manifest increased glucose production and expression of
gluconeogenic genes in the liver, indicating that STAT3 is a physiological regulator of
hepatic gluconeogenesis (4). Moreover, forced expression of an active form of STAT3 in the
liver suppressed hepatic glucose production and markedly ameliorated glucose intolerance in
insulin-resistant diabetic animals (4), suggesting that STAT3 signaling in the liver is a
potential therapeutic target in diabetes mellitus.
Glucose metabolism and lipid metabolism in the liver are closely related, such that
individuals with diabetes mellitus frequently manifest dysregulation of lipid metabolism (17).
Evaluation of the clinical utility of modulation of hepatic STAT3 signaling thus requires
characterization of the effects of activation of such signaling on lipid metabolism. Moreover,
whereas in our previous study we used a self-dimerized, oncogenic mutant of STAT3 (1) to
activate STAT3 signaling in the liver (4), it has remained unclear whether wild-type STAT3
might also have the ability to ameliorate glucose intolerance in diabetic animals. In the
present study, we have therefore investigated whether liver-specific expression of wild-type
STAT3 exerts beneficial effects on both glucose and lipid metabolism in insulin-resistant
MATERIALS AND METHODS
Mice and adenoviral vectors
The study was approved by the Animal Experimentation Committee of Kobe University.
Adenovirus vectors encoding wild-type mouse STAT3 (AxCASTAT3) (4) or β-galactosidase
(AxCALacZ) (10) were described previously. Eight-week-old male Lepr–/– mice
(C57BL/KsJ-db/db; Clea Japan), which lack functional leptin receptors and manifest
insulin-resistant diabetes (6), were injected through the tail vein with the adenovirus vectors
at the indicated number of plaque-forming units (PFU). Various metabolic parameters and
hepatic gene expression were assayed with mice in the randomly fed state 4 days after
adenovirus injection. Metabolic parameters including concentrations of blood glucose,
plasma insulin, and plasma lipids were assayed as described (10, 12).
Hepatic gene expression
Hepatic gene expression was evaluated by reverse transcription and real-time polymerase
chain reaction analysis with 36B4 mRNA as the invariant control, as described (4). The
primers used were as follows: STAT3, 5'-CCAACAGCCGCCGTAGTGAC-3' and
5'-GCCAGCCCTACCCGTACACA-3' and 5'- CGCCCAGCTTGACAAT-3'; acetyl-CoA
5'-GACAGAAGTCAAGTTCCACGCCACT-3'; and carnitine palmitoyltransferase 1 (CPT1),
5'-GCTGCTTCCCCTCACAAGTTCC-3' and 5'-GCTTTGGCTGCCTGTGTCAGTATGC-3'.
The primers for SREBP1a, SREBP1c, fatty acid synthase (FAS), stearoyl-CoA desaturase 1
(SCD1), peroxisome proliferator–activated receptor (PPAR) α, PPARγ coactivator 1α
acyl-CoA oxidase (ACO),
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