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Am J Physiol Gastrointest Liver Physiol 293: G204-G210, 2007. First published March 29, 2007; doi:10.1152/ajpgi.00021.2007
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LIVER AND BILIARY TRACT

HGF ameliorates a high-fat diet-induced fatty liver

Takashi Kosone, Hitoshi Takagi, Norio Horiguchi, Yasuyo Ariyama, Toshiyuki Otsuka, Naondo Sohara, Satoru Kakizaki, Ken Sato, and Masatomo Mori

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

Submitted 9 January 2007 ; accepted in final form 26 March 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocyte growth factor (HGF) has various effects especially on epithelial cells. However, the precise role of HGF on lipogenesis is still not fully understood. A high-fat diet was administered to HGF transgenic mice and wild-type control mice in vivo. Furthermore, recombinant human HGF (rhHGF) was administered to HepG2 cell line in vitro. We performed an analysis regarding the factors relating to lipid metabolism. An overexpression of HGF dramatically ameliorates a high-fat diet-induced fatty liver. HGF transgenic mice showed an apparently reduced lipid accumulation in the liver. The activation of microsomal triglyceride transfer protein (MTP) and apolipoprotein B (ApoB) accompanying higher triglyceride levels in the serum were found in HGF transgenic mice on a normal diet. Interestingly, this upregulation of the MTP activation became more apparent in the high-fat diet. In addition, the administration of rhHGF stimulated MTP and ApoB expression while reducing reduced the intracellular lipid content in HepG2 cell line. However, this induction of MTP and ApoB by HGF was clearly inhibited by PD98059 (MAPK inhibitor). In conclusion, the data presented in this study indicated that HGF ameliorates a high-fat diet-induced fatty liver via the activation of MTP and ApoB.

hepatocyte growth factor; fatty liver; microsomal triglyceride transfer protein; apolipoprotein B

FATTY LIVER IS A COMMON DISEASE in patients accompanied with obesity and diabetes, and one of the major causes to develop obesity and diabetes in humans is a high-fat diet.

Nonalcoholic fatty liver disease (NAFLD) has been increasing as a condition which eventually progresses to end-stage liver disease. The pathological picture resembles that of alcohol-induced liver injury, but it occurs in patients who do not abuse alcohol. NAFLD affects 10–24% of the general population in various countries. The prevalence increases to 57.5–74% in obese populations (1).

Although various ways of treating this disease have been advocated (7, 21), no definite medications have been proven to directly improve NAFLD.

NAFLD is a liver injury in which the histopathological abnormalities mimic those of alcoholic steatohepatitis (19). Hepatocyte growth factor (HGF) administration has recently been shown to improve alcoholic fatty liver (28, 29), but the precise effect of HGF on NAFLD remains to be elucidated. We therefore investigated whether or not HGF administration could possibly be effective for improving NAFLD.

HGF is a polypeptide originally characterized as a highly potent hepatocyte mitogen (10, 20). Recent studies have shown HGF to be a multifunctional cytokine that can elicit mitogenic, motogenic, and morphogenic responses in a variety of cultured epithelial cells expressing the transmembrane tyrosine kinase receptor, c-Met (5, 38).

We have developed and maintained HGF transgenic line and disclosed several phenotypes (25, 30, 32). Using this mouse model, we examined the effect of HGF in NAFLD with the high-fat diet. Moreover, subsequent studies led to the understanding that the improvement of alcoholic liver injury was followed by the upregulation of microsomal triglyceride transfer protein (MTP) and apolipoprotein B (ApoB) (28, 29). We therefore performed a further examination as follows using the MTP and ApoB in the NAFLD model.

MTP is a rate-limiting factor for the production of ApoB-containing very-low-density lipoproteins (12, 18, 37). MTP is an exclusive intracellular protein (12) and its principal role is to transfer lipids onto the ApoB polypeptides in the endoplasmic reticulum of lipoprotein-secreting cells (12).

We herein demonstrated that an overexpression of HGF dramatically ameliorated a high-fat diet-induced fatty liver in vivo. Furthermore, we showed this protective effect of HGF to be due to MTP and ApoB activation.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Transgenic mice and treatment. Transgenic mice (Tg), in which the expression of a murine HGF cDNA was driven by the metallothionein promoter and locus control regions, were generated on the inbred albino FVB/NCr genetic background (hereafter referred to as FVB) as described previously (30). Furthermore, Takayama et al. demonstrated that HGF transgene expressed in all organs and there were a number of phenotypes, such as hepatomegaly, cystic disease accompanied by focal segmental glomerulosclerosis, ulceration associated with chronic active inflammation of the rectum, and so on (25, 31–33).

Six- to 8-wk-old male Tg and FVB wild-type mice (WT) were used. All animal studies were performed according to the guidelines for animal care and use established by Institutional Review Board of Gunma University Graduate School of Medicine. WT and Tg were placed after weaning (3 wk of age) on either a high-fat diet (60% of calories derived from fat; D12492 [GenBank] , Research Diets, New Brunswick, NJ) or a normal chow diet (10% of calories derived from fat; D12450B, Research Diets). The mice were pair-fed on these diets for 4 wk.

Biochemical and histological analysis. Lipids were extracted from 50 mg of liver homogenate, and the lipid concentration per wet liver weight was measured according to the method described previously (9). For the histological analysis, liver tissue was fixed in 4% paraformaldehyde and embedded in paraffin. Alternatively, the hepatic lipids were stained by an Oil Red O method. For the protein or RNA analysis, tissue specimens were frozen in liquid nitrogen and stored at –80°C until used. Serum concentrations of alanine aminotransferase (ALT), triglyceride, and serum glucose were measured with a standard clinical autoanalyzer (Hitachi 7170; Hitachi, Tokyo, Japan). The serum insulin level was determined using an insulin radioimmunoassay kit (Shionogi, Osaka, Japan) according to the manufacturer's instructions. The serum glucose and insulin level were measured by using the samples extracted after 12 h of fasting.

ApoB in the serum or medium were determined using the ApoB ELISA kit (ALerCHEK, Portland, ME) according to the manufacturer's instructions.

RNA analysis. The human hepatocarcinoma cell, HepG2, was obtained from the American Type Culture Collection (Manassas, VA). HepG2 cells (2 x 105) were seeded in a 35-mm dish for 24 h, the medium was exchanged with serum-free DMEM (GIBCO BRL, Grand Island, NY), and the cells were then incubated overnight. Furthermore, these cells were incubated for 6 h with 40 ng/ml of the recombinant human HGF (rhHGF; R&D Systems, Minneapolis, MN), with or without 20 µM of a MAPK inhibitor, PD98059 (Sigma-Aldrich Japan K.K., Tokyo, Japan), or a phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin (Sigma-Aldrich Japan K.K.), for 1 h before HGF stimulation. RNA collection, RT-PCR, and real-time PCR methods using mice liver tissue or cells were described previously (17). The sequence details are shown in Table 1.


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  		Table 1. Sequences of primer pairs used for amplification of mRNA by real-time PCR

 
Microarray experiments. The quality of total RNA from the mouse liver tissue specimens as evaluated by A260/A280 ratio, which was at least 1.9, and by gel electrophoresis pattern, which revealed two major bands of 28S and 18S RNA. The sample labeling, microarray hybridization, washing, and scanning were performed according to the manufacturer's protocols (Affymetrix, Santa Clara, CA). Labeled cRNA was prepared and subsequently hybridized to Affymetrix MOE430A array (containing 22,690 transcripts, almost 14,500 known genes, and 4,371 expressed sequence tags). The arrays were then scanned with the GeneArray Scanner (GeneArray 2500 scanner, Affymetrix). The data obtained through GeneChip scanning was analyzed with Affymetrix Microarray Suit Software 5.0 (Affymetrix). Before the two arrays were compared, the GeneChip software program was used to normalize and scale the data for each array. The mRNA expression level of a transcript is directly related to the signal, which is a quantitative metric calculated for each probe set and measures the mean difference of the fluorescence intensity between the perfect match and the central mismatch oligonucleotides of a probe set. Change measures the probability that the expression levels of a probe set in two different arrays are the same or not. The magnitude and direction of change of a transcript were indicated as the fold change.

Hepatic MTP activity. The hepatic MTP activity was determined by using a commercial kit based on the MTP-mediated transfer of a self-quenched fluorescent neutral lipid from the core of a donor particle to an acceptor particle (Roar Biomedical, New York, NY).

Analysis of ApoB protein. For immunoprecipitation, 1,000 µg of liver tissue lysate were incubated with anti-ApoB antibody (Santa Cruz Biotechnology, Santa Cruz, CA) for 2 h on ice. After the addition of Gamma-Bind G Sepharose (Boehringer Mannheim, Mannheim, Germany) and washing in RIPA buffer, the immunoprecipitates were fractionated on 10% polyacrylamide gels (BIOCRAFT, Tokyo, Japan). A Western blot analysis was performed as described previously (17).

Determination of the intracellular lipid content. HepG2 cells were incubated in complete medium with 10% fetal bovine serum in 100-mm-diameter dishes, grown to 70% confluence, and maintained in serum-free DMEM overnight. The cells were treated by in serum-free medium for 24 h, followed by incubation with or without 50 ng/ml rhHGF in medium for 24 h. Triglyceride contents were determined in cell lysates by a colorimetric assay and were expressed as milligrams of lipid per milligram of cellular protein as described previously (36). The cell lysates were homogenized and transferred the supernatant and then mixed with chloroform-methanol and vortexed. After centrifugation, the lower layer was transferred and evaporated. We measured the triglyceride content after adding 2-propanol (Wako Chemical, Osaka, Japan).

Statistical analysis. All data were expressed as means ± SD. The statistical analysis was performed by unpaired Student t-test or by one-way ANOVA. When the ANOVA analyses were applied, differences in the mean values among the groups were examined by Fisher's multiple comparison test.


   RESULTS
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DISCUSSION
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Body weight, glucose metabolism, and serum ALT level. Although the body weights of both WT and Tg were not different, relative liver weight per body weight of Tg was significantly higher than that of WT on the normal diet (Table 2). The feed intake was not different between both the diet and mouse groups. Because it is said that abnormalities in insulin action may be involved in the pathogenesis of NAFLD, we measured the serum glucose and insulin concentration. As a result, these data between both mouse groups were not significantly different (Table 2). Moreover, the high-fat diet did not affect the serum ALT levels in both mice (Fig. 1A).


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  		Table 2. Body and liver weight and glucose metabolism

 

Figure 1
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  		Fig. 1. A: serum alanine aminotransferase (ALT) level. B and C: serum and hepatic triglyceride concentrations, respectively. Each value represents mean ± SD (n = 6 per group), *P < 0.05, **P < 0.01. D: accumulation of lipid droplets in the liver of wild-type (WT) and Tg mice, on a normal diet (Nor) or high-fat diet (High). Liver tissue samples were fixed as described in METHODS and stained with hematoxylin and eosin (a–d) and Oil Red O (e and f). a, c, and e: WT. b, d, and f: Tg. Original magnification x400.

 
Serum and hepatic triglyceride concentrations. The serum triglyceride of Tg was significantly higher than that of WT (37.2 ± 26.1 vs. 256.9 ± 191.2 mg/dl, *P < 0.05, Fig. 1B). On the other hand, the triglyceride concentration in the WT liver increased more than that of the Tg liver (61.2 ± 22.5 vs. 8.0 ± 7.5 mg/g wet liver, P < 0.01, Fig. 1C).

Furthermore, the phenotype induced by hyperlipidemia such as the fat embolism, arteriosclerosis, or pancreatitis, etc. was not observed. Moreover, no systemic inflammatory reactions including inflammation in the liver were observed either.

Histological analysis of the liver. On the normal diet, the histological findings did not differ substantially between the WT and Tg liver (Fig. 1D, a and b). However, on the high-fat diet, lipid droplets accumulated in the hepatocytes in both the perivenular and the periportal area in WT. On the other hand, in Tg, lipid droplets were localized only around the perivenular area (Fig. 1D, c–f).

Gene expression relating to oxidation and triglyceride synthesis. To elucidate the difference of gene expression between WT and Tg, we applied DNA microarrays to reveal differential mRNA expression between both mice livers. The gene expressions in the liver related to oxidation such as acyl-CoA oxidase, carnitine acetyltransferase, uncoupling protein 2, and AMP-activated protein kinase alpha 1 were not different. Moreover, the gene expressions related to triglyceride synthesis such as sterol regulatory element binding protein 1, stearoyl-CoA desaturase 1, glucose-6-phosphate dehydrogenase 2, acyl-CoA synthetase, and acetyl-CoA carboxylase beta did not differ substantially in both mouse livers, either (Table 3). These DNA microarrays results were confirmed by real-time PCR analysis (primers are shown in Table 2; data not shown). On the other hand, the transcriptome analysis in Tg liver allowed us to reveal upregulation of MTP and ApoB. HGF administration has recently been shown to improve alcoholic fatty liver by the upregulation of MTP and ApoB (28, 29). Therefore, we performed a further examination as follows for MTP and ApoB.


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  		Table 3. Expression of lipid metabolism related protein in HGF transgenic mice

 
Hepatic MTP gene expression and activity. The MTP expression (Fig. 2A) and MTP activity (Fig. 2B) in Tg were higher than those in WT on the normal and high-fat diet. Furthermore, the high-fat diet significantly increased MTP expression and MTP activity in both mice.


Figure 2
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  		Fig. 2. A: microsomal triglyceride transfer protein (MTP) mRNA expression in the liver on the normal-fat diet or high-fat diet. *P < 0.01 (n = 3) B: MTP activity in the liver on the normal and high-fat diets; *P < 0.01 (n = 3). C: apolipoprotein B (ApoB) mRNA expression in the liver on the normal and high-fat diets; *P < 0.01 (n = 3). D: ApoB protein expression in the liver on the normal and high-fat diet. E: serum ApoB content on the normal and high-fat diet. WT, white bars; Tg, black bars. *P < 0.01 (n = 6); ns., not significant.

 
Hepatic ApoB gene expression and ApoB protein content. In Tg, the ApoB expression was significantly higher than that in WT (Fig. 2C). However, a high-fat diet did not accelerate the ApoB expression. In a similar way, Western blotting showed that the level of ApoB protein in the liver increased in Tg and high-fat diet did not increase the ApoB protein level in either of the groups.

A Western blotting analysis showed that ApoB protein increased in the Tg liver (Fig. 2D). The serum ApoB concentration of Tg was significantly higher than that of WT on the normal and high-fat diet (Fig. 2E).

MTP expression and activity and ApoB expression and secretion induced by rhHGF in HepG2 cell line. The MTP expression (Fig. 3A) and activity (Fig. 3B) and the ApoB expression (Fig. 3C) and secretion (Fig. 3D) both significantly increased by rhHGF stimulation. All these effects were significantly inhibited by the coadministration of rhHGF and PD98059, whereas only PD98059 administration had no effect on these parameters (Fig. 3, A–D). On the other hand, the wortmannin treatment did not block any HGF effect (data not shown).


Figure 3
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  		Fig. 3. Effect of recombinant human hepatocyte growth factor (HGF) and PD98059 (PD) on the MTP and ApoB in HepG2 cells. A: real-time PCR analysis of mRNA of MTP. B: MTP activity. C: ApoB. D: ApoB content in the culture media. E: intracellular lipid content. Lane 1, serum-free DMEM alone (Ctrl.); lane 2, HGF 40 ng/ml; lane 3, HGF 40 ng/ml and PD98059 20 µM; lane 4, PD98059 20 µM alone. Error bars represent the standard deviation of triplicate experiments. Similar results were obtained in 3 independent experiments. *P < 0.01 compared with control; #P < 0.01 compared with HGF stimulation.

 
Intracellular triglyceride contents. The addition of rhHGF into the media induced a reduction of the intracellular lipid content (Fig. 3E). Furthermore, the pretreatment of PD95059, an MAPK inhibitor, blocked this rhHGF effect. These results indicated that HGF accelerates the lipid secretion to outside cell, and this effect seemed to act through the MAPK pathway, at least in part.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we clearly demonstrated that an overexpression of HGF dramatically ameliorates a high-fat diet-induced fatty liver in vivo, as well as the mechanism of the acceleration of lipid secretion from the liver by HGF.

In in vitro studies, HGF had been reported to regulate the lipid metabolism, such as the stimulation of lipid synthesis and lipoprotein secretion (15, 16, 24, 26, 27). On the other hand, in in vivo studies, the antidiabetic reagents pioglitazone and metformin were reported to improve alcoholic fatty liver by inducing the ApoB expression and MTP activity through c-met activation (3, 34). Moreover, Borowiak et al. (4) reported that the long-term loss of Met does lead to microvesicular steatosis in the conditional Met mutation mice liver. We also demonstrated that in NK2 transgenic mice, a massive intracellular accumulation of lipid was observed in hepatocytes at 48 h after a partial hepatectomy (22). As NK2 was thought to an HGF antagonist of a variety of biological activities (23), these two mouse models suggest that the HGF-c-Met signaling plays a crucial role in the lipid accumulation in the liver.

The hepatic triglyceride content is modulated by several factors affecting liver fatty acid synthesis and oxidation and triglyceride secretion from the liver (11). The gene expression profiles regulating oxidation, triglyceride synthesis, or secretion are shown in Table 3. There were no differences in these genes except for MTP and ApoB between WT and Tg. Furthermore, we also confirmed the expression levels of the representative genes by real-time PCR (Table 1). As a result, among the many genes regulating triglyceride oxidation, synthesis, or secretion, the gene expression of ApoB and MTP was different between WT and Tg. Furthermore, we examined these genes more closely on the RNA, protein, and activity level as previously reported (28, 29).

It has already been shown that an inhibitory effect on hepatic very-low-density lipoprotein secretion was one of the major causes of alcoholic fatty liver (6, 13, 35). A previous study showed alcoholic fatty liver to be accompanied by MTP reduction, and HGF improved fatty liver through the normalization of the MTP expression (28, 29). In our system, the MTP expression was increased more on the high-fat diet than on the normal diet (Fig. 2A). Therefore, HGF improved fatty liver regardless of the MTP expression level. Furthermore, we showed not only analyzed the protein levels related to the lipid secretion, but also that the intracellular lipid content decreased owing to HGF. However, further study would be needed to clarify the overview of HGF and the lipid metabolism.

On the other hand, the high-fat diet increased MTP mRNA but not ApoB mRNA. Because ApoB is posttranslationally controlled in their metabolic process (2, 8), a high-fat diet could not accelerate ApoB expression (Fig. 2C). However, ApoB expression in Tg was higher than that in WT. These data indicated that HGF directly affected ApoB in the transcriptional level in the different manner due to high-fat diet.

Because Ras/MAPK and PI3K cascades are thought to be the two major pathways in the HGF/c-Met signaling (39), we investigated the signaling using MAPK inhibitor PD98059 and PI3K inhibitor wortmannin in vitro. The activation of MTP and ApoB by HGF was blocked by PD98059 not but wortmannin (Fig. 3). This result indicated that the HGF/c-Met signaling regulated the MTP and ApoB expression through the MAPK pathway at least in part.

On the other hand, Tg has been reported to have several phenotypes, such as developmental anomalies (30), renal dysfunction (31), and intestinal disease (33) as well as hepatomegaly with spontaneous neoplastic transformation (25, 32). When using HGF for the treatment of fatty liver in the future, it is necessary to pay close attention to such pathological changes including hepatocarcinogenesis.

In conclusion, HGF was found to ameliorate a high-fat diet-induced fatty liver while also inducing hyperlipidemia through the acceleration of the lipid secretion system including MTP and ApoB. HGF may therefore be a potentially effective treatment for NAFLD; however, further studies are needed to elucidate whether hyperlipidemia or oncogenesis (14) might be possible side effects of HGF administration.


   ACKNOWLEDGMENTS
 
The authors thank Dr. Glenn Merlino (National Institute of Health, Bethesda, MD) for providing the HGF transgenic strain MH19 and Yuka Nakajima for assisting in the experiments.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. Takagi, Dept. of Medicine and Molecular Science, Gunma Univ. Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan (e-mail: htakagi{at}med.gunma-u.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
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 RESULTS
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 REFERENCES
 

  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 346: 1221–1231, 2002.[Free Full Text]
  2. Avramoglu RK, Adeli K. Hepatic regulation of apolipoprotein B. Rev Endocr Metab Disord 5: 293–301, 2004.[CrossRef][Web of Science][Medline]
  3. Bergheim I, Guo L, Davis MA, Lambert JC, Beier JI, Duveau. Metformin prevents alcohol-induced liver injury in the mouse: critical role of plasminogen activator inhibitor-1. Gastroenterology 130: 2099–2112, 2006.[CrossRef][Web of Science][Medline]
  4. Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C. Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA 101: 10608–10613, 2004.[Abstract/Free Full Text]
  5. Brinkmann V, Foroutan H, Sachs M, Weidner KM, Birchmeier W. Hepatocyte growth factor/scatter factor induces a variety of tissue-specific morphogenic programs in epithelial cells. J Cell Biol 131: 1573–1586, 1995.[Abstract/Free Full Text]
  6. Day CP, Yeaman SJ. The biochemistry of alcohol-induced fatty liver. Biochim Biophys Acta 1215: 33–48, 1994.[Medline]
  7. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43: S99–S112, 2006.[CrossRef][Web of Science][Medline]
  8. Fisher EA, Ginsberg HN. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J Biol Chem 277: 17377–17380, 2002.[Free Full Text]
  9. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226: 497–509, 1957.[Free Full Text]
  10. Gohda E, Tsubouchi H, Nakayama H, Hirono S, Sakiyama O, Takahashi K, Miyazaki H, Hashimoto S, Daikuhara Y. Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. J Clin Invest 81: 414–419, 1988.[Web of Science][Medline]
  11. Goldberg IJ, Ginsberg HN. Ins and outs modulating hepatic triglyceride and development of nonalcoholic fatty liver disease. Gastroenterology 130: 1343–1346, 2006.[CrossRef][Web of Science][Medline]
  12. Gordon DA, Jamil H. Progress towards understanding the role of microsomal triglyceride transfer protein in apolipoprotein-B lipoprotein assembly. Biochim Biophys Acta 1486: 72–83, 2000.[Medline]
  13. Grunnet N, Kondrup J, Dich J. Effect of ethanol on lipid metabolism in cultured hepatocytes. Biochem J 228: 673–681, 1985.[Web of Science][Medline]
  14. Horiguchi N, Takayama H, Toyoda M, Otsuka T, Fukusato T, Merlino G, Takagi H, Mori M. Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine. Oncogene 21: 1791–1799, 2002.[CrossRef][Web of Science][Medline]
  15. Kaibori M, Kwon AH, Nakagawa M, Wei T, Uetsuji S, Kamiyama Y, Okumura T, Kitamura N. Stimulation of liver regeneration and function after partial hepatectomy in cirrhotic rats by continuous infusion of recombinant human hepatocyte growth factor. J Hepatol 27: 381–390, 1997.[CrossRef][Web of Science][Medline]
  16. Kaibori M, Kwon AH, Oda M, Kamiyama Y, Kitamura N, Okumura T. Hepatocyte growth factor stimulates synthesis of lipids and secretion of lipoproteins in rat hepatocytes. Hepatology 27: 1354–1361, 1998.[CrossRef][Web of Science]
  17. Kosone T, Takagi H, Kakizaki S, Sohara N, Horiguchi N, Sato K, Yoneda M, Takeuchi T, Mori M. Integrative roles of transforming growth factor-alpha in the cytoprotection mechanisms of gastric mucosal injury. BMC Gastroenterol 6: 22, 2006. (http://www.biomedcentral.com/1471-230X/6/22)[CrossRef][Medline]
  18. Leung GK, Veniant MM, Kim SK, Zlot CH, Raabe M, Bjorkegren J, Neese RA, Hellerstein MK, Young SG. A deficiency of microsomal triglyceride transfer protein reduces apolipoprotein B secretion. J Biol Chem 275: 7515–7520, 2000.[Abstract/Free Full Text]
  19. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55: 434–438, 1980.[Web of Science][Medline]
  20. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature 342: 440–443, 1989.[CrossRef][Medline]
  21. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37: 1202–1219, 2003.[CrossRef][Web of Science][Medline]
  22. Otsuka T, Horiguchi N, Kanda D, Kosone T, Yamazaki Y, Yuasa K, Sohara N, Kakizaki S, Sato K, Takagi H, Merlino G, Mori M. Overexpression of NK2 inhibits liver regeneration after partial hepatectomy in mice. World J Gastroenterol 11: 7444–7449, 2005.[Medline]
  23. Otsuka T, Jakubczak J, Vieira W, Bottaro DP, Breckenridge D, Larochelle WJ, Merlino G. Disassociation of met-mediated biological responses in vivo: the natural hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but facilitates metastasis. Mol Cell Biol 20: 2055–2065, 2000.[Abstract/Free Full Text]
  24. Roos F, Ryan AM, Chamow SM, Bennett GL, Schwall RH. Induction of liver growth in normal mice by infusion of hepatocyte growth factor/scatter factor. Am J Physiol Gastrointest Liver Physiol 268: G380–G386, 1995.[Abstract/Free Full Text]
  25. Sakata H, Takayama H, Sharp R, Rubin JS, Merlino G, LaRochelle WJ. Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal development, and tumor formation in transgenic mouse livers. Cell Growth Differ 7: 1513–1523, 1996.[Abstract]
  26. Shao Q, Arakaki N, Ohnishi T, Nakamura O, Daikuhara Y. Effect of hepatocyte growth factor/scatter factor on lipogenesis in adult rat hepatocytes in primary culture. J Biochem (Tokyo) 119: 940–946, 1996.[Abstract/Free Full Text]
  27. Shiota A, Yamashita Y, Fujise N, Masunaga H, Yasuda H, Higashio K. A deleted form of human hepatocyte growth factor stimulates hepatic lipogenesis and lipoprotein synthesis in rats. Pharmacol Res 42: 443–452, 2000.[CrossRef][Web of Science][Medline]
  28. Sugimoto T, Yamashita S, Ishigami M, Sakai N, Hirano K, Tahara M, Matsumoto K, Nakamura T, Matsuzawa Y. Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats. J Hepatol 36: 157–162, 2002.[Web of Science][Medline]
  29. Tahara M, Matsumoto K, Nukiwa T, Nakamura T. Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats. J Clin Invest 103: 313–320, 1999.[Web of Science][Medline]
  30. Takayama H, La Rochelle WJ, Anver M, Bockman DE, Merlino G. Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development. Proc Natl Acad Sci USA 93: 5866–5871, 1996.[Abstract/Free Full Text]
  31. Takayama H, LaRochelle WJ, Sabnis SG, Otsuka T, Merlino G. Renal tubular hyperplasia, polycystic disease, and glomerulosclerosis in transgenic mice overexpressing hepatocyte growth factor/scatter factor. Lab Invest 77: 131–138, 1997.[Web of Science]
  32. Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, Aaronson SA, Merlino G. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc Natl Acad Sci USA 94: 701–706, 1997.[Abstract/Free Full Text]
  33. Takayama H, Takagi H, Larochelle WJ, Kapur RP, Merlino G. Ulcerative proctitis, rectal prolapse, and intestinal pseudo-obstruction in transgenic mice overexpressing hepatocyte growth factor/scatter factor. Lab Invest 81: 297–305, 2001.[Web of Science]
  34. Tomita K, Azuma T, Kitamura N, Nishida J, Tamiya G, Oka A, Inokuchi S, Nishimura T, Suematsu M, Ishii H. Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met. Gastroenterology 126: 873–885, 2004.[CrossRef][Web of Science]
  35. Venkatesan S, Ward RJ, Peters TJ. Effect of chronic ethanol feeding on the hepatic secretion of very-low-density lipoproteins. Biochim Biophys Acta 960: 61–66, 1988.[Medline]
  36. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113: 159–170, 2003.[CrossRef][Web of Science][Medline]
  37. Wetterau JR, Gregg RE, Harrity TW, Arbeeny C, Cap M, Connolly F, Chu CH, George RJ, Gordon DA, Jamil H, Jolibois KG, Kunselman LK, Lan SJ, Maccagnan TJ, Ricci B, Yan M, Young D, Chen Y, Fryszman OM, Logan JV, Musial CL, Poss MA, Robl JA, Simpkins LM, Slusarchyk WA, Sulsky R, Taunk P, Magnin DR, Tino JA, Lawrence RM, Dickson JK Jr, Biller SA. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 282: 751–754, 1998.[Abstract/Free Full Text]
  38. Zarnegar R, Michalopoulos GK. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 129: 1177–1180, 1995.[Free Full Text]
  39. Zhang YW, Vande Woude GF. HGF/SF-met signaling in the control of branching morphogenesis and invasion. J Cell Biochem 88: 408–417, 2003.[CrossRef][Web of Science][Medline]



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