[Non-alcoholic steatohepatitis (NASH). 2. Insulin resistance and NASH].
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Fatty Liver↗
Biomedical subjects
Masafumi Ono
Publications and source records attributed to Masafumi Ono.
Clinical features of nonalcoholic steatohepatitis in Japan: Evidence from the literature.
Metabolic syndrome, that is, obesity, hypertension, hyperlipidemia, and insulin resistance with hyperinsulinemia, is a new disease entity prevailing worldwide, and nonalcoholic steatohepatitis (NASH) is believed to be a hepatic expression of this syndrome. NASH is characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Indeed, 90% of NASH has been revealed to be complicated by visceral obesity, and two-thirds of NASH patients fulfill the criteria of metabolic syndrome. Therefore, a variety of lifestyle-related diseases such as obesity, hypertension, hyperlipidemia, and diabetes mellitus may share the same background. NASH is most prevalent and well characterized in Caucasians; however, little is known about its occurrence in Asia-Oceania, because obesity has not been frequent in countries in these areas. Obesity is expected to become a serious social problem in Asia-Oceania in the next two decades, so we need to prevent a corresponding increase of NASH. For that purpose, we need to know much about not only NASH but also ourselves. To elucidate the status of NASH in Japan, recent progress in the study of NASH in Japan is reviewed in this article.
Blood Glucose↗
[NASH and metabolic syndrome].
Visceral obesity and insulin resistance are typical clinical features of nonalcoholic steatohepatitis (NASH) characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Indeed, 90% of NASH revealed to be complicated with visceral obesity, and two thirds of NASH patients fulfill the criteria of metabolic syndrome. Therefore, NASH could be regarded as the hepatic manifestation of metabolic syndrome, and a variety of life-style related diseases such as obesity, hypertension, hyperlipidemia and diabetes mellitus could be used for detecting
Fatty Liver↗
In vivo imaging of hepatic fatty acid metabolism in patients with nonalcoholic steatohepatitis using semiquantative (123)I-BMIPP liver scan.
Recent progress of studies in NASH displays multi-disciplinary characters of the pathogeneses. Despite these advances, the strategic use of imaging modalities such as CT, US, and MRI, remains a relatively low priority in clinical situations, because these can only visualize the presence of fatty infiltration to the hepatic parenchyma, impossible to figure out the dynamic function of NASH liver. Morphological alteration such as CT value, MR signal intensity and echo-grade do not distinguish NASH from simple fatty liver. In this presentation, from a radiologic viewpoint, we show the feasibility of in vivo fatty acid imaging with (123)I-beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP). BMIPP is an (123)I labeled fatty acid analog for imaging damaged myocardium, using conventional nuclear imaging equipment. Under normal conditions, the energy source for myocardial utilization is dependent on the beta-oxidation of fatty acids. For energy production in ischemic myocardium, the drastic switch from reduced beta-oxidation of fatty acids to glucose metabolism is well known. BMIPP can detect the area of reduced fatty acids metabolism on myocardial imaging and the data can be converted into semiquantitative analysis. Therefore, we speculate that the use of BMIPP to in vivo hepatic imaging in NASH could highlight a lot of matters of NASH. Details of this presentation include: (1) Hepatic imaging with BMIPP; (2) Clearance of BMIPP from NASH liver; (3) semiquantitative analysis of hepatic BMIPP clearance and clinical features of NASH; (4) Profiles of NASH categorized by BMIPP imaging and (5) Preliminary data of BMIPP clearance in patients with Tamoxifen-induced NASH. The core of our stance in this presentation is searching for valuable advice on clinical use of BMIPP in patients with NASH from specialists in the field of HEPATOLOGY.
Journal Article↗
Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis.
BACKGROUND/AIMS: The pathogenesis of non-alcoholic steatohepatitis (NASH) is poorly understood. The aim of this study was to examine genetic influences on NASH pathogenesis. METHODS: Blood samples from 63 patients with biopsy-proven NASH and 150 healthy controls were analyzed by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Two functional polymorphisms were studied: the -493 G/T polymorphism in the promoter of microsomal triglyceride transfer protein (MTP) and the 1183 T/C polymorphism in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD). RESULTS: NASH patients had a much higher incidence of the MTP gene G allele (P=0.001) and of the G/G genotype (P=0.002) compared to the controls. Fat occupied more area in liver lobules and the stage of NASH was advanced in patients with the G/G-genotype than in patients with G/T-genotype (P=0.04). NASH patients also had a higher incidence of the MnSOD T/T genotype (P=0.016). CONCLUSIONS: The G allele in the MTP promoter leads to decreased MTP transcription, less export of triglyceride from hepatocytes, and greater intracellular triglyceride accumulation. The T allele in MnSOD mitochondrial targeting sequence leads to less transport of MnSOD to the mitochondria. Therefore, functional polymorphisms in MTP and MnSOD may be involved in determining susceptibility of NASH.
Adult↗
Increased susceptibility to liver injury after hemorrhagic shock in rats chronically fed ethanol: role of nuclear factor-kappa B, interleukin-6, and granulocyte colony-stimulating factor.
Chronic ethanol use preceding severe trauma and hemorrhagic shock (HS) is associated with an increased incidence of multiorgan failure (MOF) and death; however, the molecular basis for this increased susceptibility is unknown. We previously demonstrated that production of interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF), mediated by nuclear factor-kappa B (NF-kappa B), each make essential contributions to organ injury and inflammation in a rodent model of controlled HS, and we proposed in this study to examine the hypothesis that the increased susceptibility to MOF after shock/trauma in the setting of chronic ethanol use is due to an exaggerated activation of NF-kappa B and production of these proinflammatory cytokines. We observed increased HS-induced liver injury 4 h after resuscitation in rats fed the ethanol-containing Lieber-DeCarli liquid diet for 8 weeks compared with rats fed the control liquid diet (3-fold increase in serum alanine aminotransferase [ALT], P = 0.008, and 2-fold increase in focal liver necrosis, P = 0.005). The increased liver injury in the ethanol-fed HS rats was accompanied by a 70% increase in liver NF-kappa B activation (P < 0.05), a 3- to 5-fold increase in hepatocyte and Kupffer cell production of IL-6 and G-CSF (P < 0.05 for each), and a 2-fold increase in neutrophil infiltration (P < 0.005) compared with the control diet-fed HS rats. Thus, increased susceptibility to HS-induced liver injury in the setting of chronic ethanol use may be mediated, at least in part, by increased NF-kappa B activation resulting in increased local production of IL-6 and G-CSF and increased infiltration of neutrophils, which can damage liver cells directly and contribute to impaired sinusoidal blood flow.
Animals↗
Polymorphisms of interleukin-1 beta and beta 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis.
BACKGROUND: Obesity, hypertriglyceridemia, and diabetes have been reported as frequent complications observed in patients with nonalcoholic steatohepatitis (NASH) in Western countries. The aim of this study was to investigate the genetic predisposition on NASH pathogenesis in the Japanese population. METHODS: Genotypes of two previously described functional polymorphisms-beta3-adrenergic receptor 190 T/A polymorphism, which results in Trp64Arg (W64R) amino acid replacement, and interleukin-1beta-511 T/C polymorphism in the promoter sequence-were determined in 63 Japanese NASH patients and 100 healthy volunteers using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: beta3-adrenergic receptor R allele frequency and the R/- (W/R and R/R) genotype frequency were significantly higher in NASH patients than those in control subjects. Interleukin-1beta-511 T allele frequency and the T/T genotype frequency were significantly higher in NASH patients than those in control subjects. Obesity, hypertriglyceridemia, and hyperinsulinemia were associated with NASH patients with the R/- genotype, whereas an increase in fasting plasma glucose level and a decrease in insulinogenic index were associated with NASH patients with the W/W genotype. CONCLUSION: This study confirmed the contribution of obesity, glucose intolerance, and hypertriglyceridemia to NASH development in the Japanese population. In addition to these factors, genetic predispositions to obesity and inflammation in the Japanese population were shown to contribute much to the development of NASH.
Aged↗
[What is NASH?].
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Diagnosis, Differential↗
Protective effect of 3-methyl-1-phenyl-2-pyrazolin-5-one, a free radical scavenger, on acute toxicity of paraquat in mice.
Paraquat poisoning results in damages of multiple organs including liver, kidney and lung, and antioxidants have been proven to have protective effects. As a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), was introduced to clinical use recently, its protective effect was studied on acute toxicity of paraquat in male ddY mice. When paraquat (175 mg/kg) were given orally, the survival rate was only 8% on the 6th day of paraquat ingestion in Control Group mice. Protective effect of MCI-186 was most evident and the survival rate was 42% on the 6th day and 38% on the 14th day of paraquat ingestion, respectively, when mice were treated immediately. A delay of 30 min in treatment resulted in an abrupt reduction of the survival rate. These results suggested that MCI-186 used in acute phase of paraquat intoxication might serve as a clinically available antidote for attenuating paraquat toxicity.
Animals↗
Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice.
Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
Acyl-CoA Dehydrogenase↗
A novel type hypertriglyceridemia observed in FLS mice.
The unique inborn hypertriglyceridemia seen in FLS (fatty liver Shionogi) mice was relieved by the administration of purified apolipoprotein (apo) C-II. Lipoprotein lipase (LPL) and its cofactor, apoC-II, play a pivotal role in VLDL metabolism. Therefore, we investigated the genetic background involved in this hypertriglyceridemia. Plasma levels of TG and total cholesterol as well as LPL activity were measured in male FLS mice and C57/BL6J mice. Agarose gel electrophoresis and fast protein liquid chromatography were used to analyze the lipoprotein profile. A cross experiment was done to determine the genetic background of hypertriglyceridemia observed in FLS mice. cDNA sequences of apoC-II and apoC-III of FLS mice were determined. Prealpha-lipoprotein was the predominant lipoprotein class in FLS mouse plasma. LPL activity remained in the range observed in C57/BL6J mice, and purified apoC-II transiently relieved FLS mice from hypertriglyceridemia. Prealpha-lipoproteinemia was inherited in an autosomal recessive manner. ApoC-III appeared to be a causal factor for this unique hypertriglyceridemia. Microsatellite analysis, however, revealed that the responsible chromosome was not 7; rather, apoC-III mapped onto chromosome 9. Therefore, we suggest apoC-III as a candidate causative factor for the hypertriglyceridemia observed in FLS mice because an excessive amount of apoC-III attenuates LPL activity in vivo and in vitro.
Animals↗
Low socioeconomic status and coronary artery disease.
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Body Mass Index↗
Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration.
Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Recently, aromatase-deficient (ArKO, Ar-/-) mice lacking intrinsic estrogen was developed and the molecular mechanism involved in progression of massive hepatic steatosis in estrogen-deficiency was elucidated; impairment in hepatic fatty acid beta-oxidation of peroxisomes, microsomes and mitochondria. This impairment is latent, but is potentially serious, because hepatic energy supply depends greatly on fatty acid beta-oxidation. Therefore in the present study, we tried to conquer impaired hepatic fatty acid beta-oxidation by administrating bezafibrate, a potent peroxisome proliferator, to Ar-/- mice through activating fatty acid beta-oxidation via the peroxisome proliferator activated receptor-alpha mediated signaling pathway. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase in mitochondria, essential enzymes in fatty acid beta-oxidation by administration of bezafibrate. Severe hepatic steatosis observed in Ar-/- mice regressed dramatically. Consistent findings were obtained in the in vitro assays of fatty acid beta-oxidation activity. These findings demonstrate that bezafibrate is capable of restoring impaired fatty acid beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha mediated signaling pathway and is potent enough to regress severe hepatic steatosis in mice deficient in intrinsic estrogen.
Journal Article↗
Thymosin alpha1 accelerates restoration of T cell-mediated neutralizing antibody response in immunocompromised hosts.
Thymosin alpha1 is a biological response modifier that has been used clinically for the treatment of chronic hepatitis B viral infection. Both immunomodulatory and immediate intracellular mechanisms have been postulated to explain the effect of thymosin alpha1 on hepatocytes infected with hepatitis B virus (HBV). Here, we established a new animal model and the related suitable conditions to access the thymosin activity by means of measuring the production of neutralizing antibody against hepatitis B surface antigen (HBsAg). We proved that chemically synthesized thymosin alpha1 restored the T cell-mediated antibody production following its suppression in mice by 5-fluorouracil (5-FU), and found that thymosin alpha1 showed activity at a low dose of 30 microg/kg. Further studies utilizing the flowcytometric analysis showed that thymosin alpha1 at this dose accelerated the replenishment and maturation of thymocytes while the expression of Smoothened (Smo) of the Hedgehog (Hh)-signaling in CD4-CD8- thymocytes, the potent negative regulator of proliferative responses, was not affected. The restoration of some of the defects in the host defense systems may facilitate elimination of infectious agents, and the present study provides a novel model to define the restoration of T cell-mediated immune responses to hepatitis B virus in vivo.
Adjuvants, Immunologic↗
Estrogen deficiency results in enhanced expression of Smoothened of the Hedgehog signaling in the thymus and affects thymocyte development.
Aromatase is an essential enzyme for estrogen synthesis. We investigated the role of estrogen in thymocyte development using aromatase-deficient (ArKO) mice. Like its role as a regulator of bone metabolism through regulating osteoprotegerin (OPG) production, estrogen is involved in the processes of thymocyte development although aromatase mRNA was not detectable in the thymus. Thymic regression and reduced cellularity were evident in ArKO mice. The major difficulties in thymocyte development of ArKO mice were observed during the CD44+ CD25- stage at the cortico-medullary junction and during the CD44- CD25- stage at the subcapsular region where the estrogen receptor was expressed in the stromal cells. The proportion of thymocytes during the CD44+ CD25- stage was reduced. The progression of CD44- CD25+ cells to the CD44- CD25- stage was accelerated in ArKO mice possibly due to insufficient osteoprotegerin production in estrogen-deficiency. However, the expression of Smoothened of the Hedgehog signaling was enhanced in CD4- CD8- double negative cells. This enhancement may result in impaired progression of CD44- CD25- cells to the CD4+ CD8+ double positive stage and impaired proliferation of CD4+ CD8+ double positive cells since Smoothened (Smo) is known to arrest cells as non-proliferating cells. This could be the reason why the proportion of CD3+ TCRbeta(high) cells during the late phase of thymocyte maturation was reduced in ArKO mice. From these observations, we propose that estrogen supports thymocyte development and maturation at many stages through many regulatory pathways including the sonic hedgehog- and the osteoprotegerin ligand (OPGL)-mediated signaling.
Animals↗
Tamoxifen-induced nonalcoholic steatohepatitis in breast cancer patients treated with adjuvant tamoxifen.
OBJECTIVE: The benefits of 5-year tamoxifen administration for patients with estrogen receptor-positive breast cancer undoubtedly outweigh the risk of any adverse effects. Massive hepatic steatosis is an example of its side effects. Here we show risk factors for the development of massive hepatic steatosis and describe a representative clinical course of these patients treated with fibrates for the first time. METHODS: Computed tomography (CT) numbers of the liver and spleen were measured and correlated to body mass index (BMI) and pregnanetriol/pregnanediol ratio in urine (P3/P2 ratio). PATIENTS: We enrolled 56 premenopausal women treated with breast conservation treatment. They received oral tamoxifen (40 mg/day for 2 to 3 years) as adjuvant endocrine therapy with systemic chemotherapy. RESULTS: Serum estradiol level in 48 of 56 patients treated with tamoxifen was less than 10 pg/ml. The ratio of hepatic CT number to splenic CT number<0.9 was related to increased BMI (>23.6 kg/sqm) and reduced P/P2 ratio (<1). Fibrates are potent enough to improve hepatic steatosis in tamoxifen-induced hepatic steatosis. CONCLUSION: P3/P2 ratio<1 was related to sufficient blockade of estrogen receptor proven by the development of massive hepatic steatosis. Therefore, we propose that tamoxifen is not a mere antagonist of estrogen, but it may also suppress estrogen synthesis when estrogen receptor is blocked sufficiently. The undetectable level of serum estrogen in tamoxifen-treated premenopausal women may partially explain why tamoxifen was so effective in estrogen receptor-positive early breast cancer.
Adult↗