Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model

Shindo, Nobuyasu; Fujisawa, Tomomi; Sugimoto, Ken; Nojima, K.; Oze-Fukai, Aya; Yoshikawa, Yuki; Wang, Xiang; Yasuda, Osamu; Ikegami, Hiroshi; Rakugi, Hiromi

doi:10.1016/j.jhep.2009.12.033

Cited by 54 publications

(53 citation statements)

References 23 publications

(31 reference statements)

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“…These results indicate that the export of hepatic lipid is genetically impaired in FLS mice, consistent with previous reports [19,24]. The pathophysiology of fatty liver formation in FLS mice is unclear, but genetic induction of microsomal triglyceride transfer protein prevents hepatic fat accumulation and glucose intolerance [24].…”

Section: Discussionsupporting

confidence: 92%

Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Tagawa

Irie

Itoh

et al. 2015

Diabetes Research and Clinical Practice

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Section: Discussionsupporting

confidence: 92%

Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Tagawa

Irie

Itoh

et al. 2015

Diabetes Research and Clinical Practice

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“…41,42 Similarly, impairment of VLDL synthesis has been implicated as a possible contributor to fat accumulation in hepatocytes in a polygenic mouse model of NASH. 43 As in the current study, lipid accumulation occurred in this mouse model despite reduction of SREBP-1c and FAS expression. Although a defect of hepatic mitochondrial b-oxidation reflected by a repression of CPT-1 might also be relevant in this model, a reduction of VLDL production due to low MTP levels was identified as the major cause.…”

Section: Discussionsupporting

confidence: 72%

“…Steatosis and insulin resistance in this mouse model of NASH were largely improved by overexpression of MTP, which resulted in a rescue of VLDL production. 43 Notably, rescue of MTP expression not only improved steatosis in this model but also reduced signs of inflammation. In further support of the relevance of MTP in the development of steatosis, inhibition of MTP has been shown to contribute to drug-or alcoholinduced hepatic steatosis.…”

Section: Discussionmentioning

confidence: 79%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

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Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

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“…The pattern of low serum TG and high hepatic TG levels found in Mir122a -/-mice seems to indicate impaired MTTP expression and VLDL assembly (23,24). This pattern is commonly found in patients infected with HCV genotype 3 (27) and in fatty liver Shionogi (FLS) mice (28). Similar to FLS mice, Mir122a -/-mice also have a slight impairment of glucose tolerance, although serum glucose levels were not significantly affected (Supplemental Figure 3B).…”

Section: A Mir122a Homozygous Mutant Mouse Strain Displays Features Omentioning

confidence: 81%

MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis

Tsai¹,

et al. 2012

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MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a -/-livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a -/-mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.

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Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model

Cited by 54 publications

References 23 publications

Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis

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