Increased expression of PPARγ in high fat diet-induced liver steatosis in mice

Inoue, Mitsutaka; Ohtake, Takaaki; Motomura, Wataru; Takahashi, Nobuhiko; Hosoki, Yayoi; Miyoshi, Shigeki; Suzuki, Yôichi; Saito, Hiroyuki; Kohgo, Yutaka; Okumura, Toshikatsu

doi:10.1016/j.bbrc.2005.08.070

Cited by 332 publications

(278 citation statements)

References 31 publications

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“…It has been reported that PPARg is an important determinant of hepatic fat accumulation and that hepatic PPARg expression is increased in experimental models of fatty liver disease. [30][31][32] In the present study, 12-month-old TSOD mice exhibited increased hepatic mRNA levels for PPARg compared with TSNO mice of the same age. Furthermore, the hepatic staining intensity by CYP2E1 immunostaining is slightly greater in TSOD mice than in TSNO mice at both 6 and 12 months of age (Supplementary Figure 5).…”

Section: Discussionsupporting

confidence: 53%

Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome

Nishida

Tsuneyama

Fujimoto

et al. 2013

Laboratory Investigation

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Metabolic syndrome is a worldwide healthcare issue and a dominant risk factor for the development of incurable diseases that affect the entire body. The hepatic manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). The basic pathogenesis of NAFLD/NASH remains controversial because it is difficult to clarify the disease process of NASH on the basis of metabolic syndrome alone. To determine the pathogenesis and effective treatment, an excellent animal model of NASH is required. Tsumura Suzuki obese diabetes (TSOD) male mice spontaneously develop diabetes mellitus, obesity, glucosuria, hyperglycemia, and hyperinsulinemia without any special treatments such as gene manipulation. In this study, we examined the histopathological characteristics of visceral fat and liver of 56 male TSOD mice aged 4-17 months and 9 male Tsumura Suzuki non-obesity (control) mice aged 6-12 months. In the visceral fat, enlargement of adipocytes and perivascular and pericapsular CD8-positive lymphoid aggregation were observed in 4-month-old mice. Abnormal expression of tumor necrosis factor-a, interleukin-6, and lipid peroxidation endo products was observed in macrophages. In the liver, microvesicular steatosis, hepatocellular ballooning, and Mallory bodies were observed in 4-month-old mice, with severity worsening with increasing time. These pathological findings in the liver mimic those seen in patients with NASH. Interestingly, small liver nodules with high cellularity and absence of portal tracts were frequently observed after 12 months. Most of them showed nuclear and structural atypia, and mimicked human hepatocellular carcinoma. The degree of steatosis in the non-tumor portions of the liver improved when the liver nodules developed. These findings were not observed in control mice. Here, we report that TSOD male mice spontaneously developed NAFLD without any special treatment, and that these mice are a valuable model for assessing NASH and NASH carcinogenesis owing to metabolic syndrome.

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Section: Discussionsupporting

confidence: 53%

Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome

Nishida

Tsuneyama

Fujimoto

et al. 2013

Laboratory Investigation

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“…9,10 However, the dietary fatty acid compositions were not described in these studies. In the current study, fish oil further increased PPAR␥ and target gene mRNAs, when given to mice fed high-safflower oil diet but not to mice fed high-butter diet.…”

Section: Discussionmentioning

confidence: 97%

“…6,7 C57BL/6J mice also develop fatty liver in response to an HF diet. [8][9][10] However, they are resistant to sucrose/fructose-induced fatty liver because they possess adenine Ϫ468 bp from the putative 5Ј end of the sterol regulatory element-binding protein (SREBP)-1c gene. 11 Mice with guanine at this site show increased liver SREBP-1c messenger RNA (mRNA) in response to a high-fructose diet, whereas mice with adenine do not.…”

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confidence: 99%

Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice

Yamazaki

Nakamori²,

Sasaki³

et al. 2007

Hepatology

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Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oilinduced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPAR␥) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. Conclusion: The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPAR␥.

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“…Since the expression of enzymes responsible for lipid synthesis were reduced dramatically following 3 weeks of MCDD feeding (data not shown), we speculated that the observed steatosis was the result of enhanced lipid storage. The class B scavenger receptor CD36 has been shown to facilitate the uptake of long chain fatty acids by endothelial cells as well as macrophages, and recent data suggests that this receptor plays a role in hepatic steatosis induced by feeding a high fat diet (28,29). Another member of the toll-like receptor family, TLR-2, has been shown to play a role in lipid trafficking via uptake of diacylated lipoproteins (30), a process that requires CD36 (21).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

Rivera

Adegboyega

Rooijen

et al. 2007

Journal of Hepatology

594

509

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BACKGROUND/AIMS-Studies in animal models and humans suggest a link between endotoxemia and non-alcoholic steatohepatitis. Since Kupffer cells are responsible for clearing endotoxin and are activated via endotoxin interaction with Toll-like receptor 4 (TLR-4), we examined the relationship between hepatic TLR-4 expression and Kupffer cell content during the genesis of steatohepatitis.METHODS-Male C57BL/6, C3H/HouJ and TLR-4 mutant C3H/HeJ mice were fed control or methionine/choline-deficient diet (MCDD). In one group of C57BL/6 mice, Kupffer cells were depleted by weekly intravenous injections of clodronate liposomes. After 3 weeks, serum ALT activity and portal endotoxin levels were measured. Real-time PCR was used to examine mRNA expression of TLR-4, TLR-2, CD14, MD-2, TGFβ, TNFα CD36 PPAR-α, liver fatty acid binding protein (L-FABP) and collagen α1.RESULTS-We observed histological evidence typical of steatohepatitis, portal endotoxemia and enhanced TLR-4 expression in wild type mice fed MCDD. In contrast, injury and lipid accumulation markers were significantly lower in TLR-4 mutant mice. Destruction of Kupffer cells with clodronate liposomes blunted histological evidence of steatohepatitis and prevented increases in TLR-4 expression.CONCLUSIONS-These findings demonstrate the importance of TLR-4 signaling and underscore a direct link between TLR-4 and Kupffer cells in the pathogenesis of steatohepatitis.

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Increased expression of PPARγ in high fat diet-induced liver steatosis in mice

Cited by 332 publications

References 31 publications

Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome

Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome

Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

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