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Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis.

ABSTRACT: Nonalcoholic steatohepatitis (NASH) is a major health problem since it often leads to hepatocellular carcinoma. However, the underlying mechanisms of NASH development and subsequent fibrosis have yet to be clarified. We compared comprehensive lipidomic profiles between mice with high fat diet (HFD)-induced steatosis and STAM mice with NASH and subsequent fibrosis. The STAM mouse is a model that demonstrates NASH progression resembling the disease in humans: STAM mice manifest NASH at 8 weeks, which progresses to fibrosis at 12 weeks, and finally develop hepatocellular carcinoma. Overall, 250 lipid molecules were detected in the liver using liquid chromatography-mass spectrometry. We found that STAM mice with NASH presented a significantly higher abundance of sphingolipids and lower levels of triacylglycerols than the HFD-fed control mice. The abundance of certain fatty acids in phospholipid side chains was also significantly different between STAM and control mice, although global levels of phosphatidylcholines and phosphatidylethanolamines were comparable. Finally, increase in levels of acylcarnitines and some diacylglycerols was observed in STAM mice toward the fibrosis stage, but not in age-matched control mice. Our study provides insights into the lipid status of the steatotic, NASH, and fibrotic liver that would help elucidate the molecular pathophysiology of NASH progression.

SUBMITTER: Saito K

PROVIDER: S-EPMC4542161 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis.

Saito Kosuke K Uebanso Takashi T Maekawa Keiko K Ishikawa Masaki M Taguchi Ryo R Nammo Takao T Nishimaki-Mogami Tomoko T Udagawa Haruhide H Fujii Masato M Shibazaki Yuichiro Y Yoneyama Hiroyuki H Yasuda Kazuki K Saito Yoshiro Y

Scientific reports 20150820

Nonalcoholic steatohepatitis (NASH) is a major health problem since it often leads to hepatocellular carcinoma. However, the underlying mechanisms of NASH development and subsequent fibrosis have yet to be clarified. We compared comprehensive lipidomic profiles between mice with high fat diet (HFD)-induced steatosis and STAM mice with NASH and subsequent fibrosis. The STAM mouse is a model that demonstrates NASH progression resembling the disease in humans: STAM mice manifest NASH at 8 weeks, wh ...[more]

PMID: 26289793

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Project description:Background and aimsThe augmenter of liver regeneration (ALR) protein is critical for lipid homeostasis and mitochondrial function. We investigated high-fat/high-carbohydrate (HF/HC) diet-induced nonalcoholic fatty liver disease (NAFLD) in wild-type (WT), hepatocyte-specific ALR-knockout (ALR-H-KO), and ALR-heterozygous (ALR-H-HET) mice. ALR was measured in serum of human nonalcoholic steatohepatitis (NASH) and NASH-induced cirrhosis (serum and liver).Approach and resultsHF/HC feeding decreased ALR expression in all groups of mice. The otherwise normal ALR-H-HET mice gained more weight and steatosis than WT mice when challenged metabolically with the HF/HC diet; ALR-H-KO mice gained the least weight and had the least steatosis. These findings were consistent with correspondingly increased triglycerides and cholesterol and altered expression of carnitine palmitoyltransferase 1a, sterol regulatory element-binding protein, acetyl coenzyme A carboxylase, and fatty acid synthase. All HF/HC-fed mice developed insulin resistance, the magnitude being lower in ALR-H-KO mice. HF/HC-fed ALR-H-HET mice were more resistant to glucose challenge than WT or ALR-H-KO mice. The frequency of tumor necrosis factor alpha-producing, interleukin 6 (IL6)-producing, and IL17-producing cells was greater in ALR-H-KO than ALR-H-HET and lowest in WT mice. HF/HC feeding did not increase their number in ALR-H-KO mice, and the increase in ALR-H-HET was greater than that in WT mice except for IL17 cells. Cluster of differentiation 25-positive (CD25+ ) forkhead box P3-positive CD4+ regulatory T-cell frequency was lower in ALR-H-HET than WT mice and further reduced in ALR-H-KO mice; HF/HC reduced regulatory T-cell frequency only in WT mice. HF/HC-fed ALR-H-HET, but not WT, mice developed fibrosis; and ALR-H-KO mice progressed to cirrhosis. White adipose tissue of HF/HC-fed ALR-deficient mice developed strong inflammation, indicating bidirectional interactions with the liver. Hepatic and serum ALR levels were significantly reduced in patients with NASH-cirrhosis. Serum ALR was also significantly lower in patients with NASH.ConclusionsHepatic ALR deficiency may be a critical predisposing factor for aggressive NAFLD progression.

Dataset Information

Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis.

Publications

Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis.

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