Apolipoprotein CIII Overexpressing Mice Are Predisposed to Diet-Induced Hepatic Steatosis and Hepatic Insulin Resistance

Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high‐fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemic‐euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C‐ϵ activation, and decreased insulin‐stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD‐fed ApoC3Tg mice could be attributed to a ≈70% increase in hepatic triglyceride uptake and ≈50% reduction hepatic triglyceride secretion. Conclusion: These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet‐induced NAFLD and hepatic insulin resistance. (HEPATOLOGY 2011;)

• Publication year

  2011

• Venue

  Hepatology

• Publication date

  2011-08-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/hep.24571PMID 21793029PMCID 3205235
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease.

  2010influential reference
• Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease.

  2010cited by this paper
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• Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease.

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• Design and validation of a histological scoring system for nonalcoholic fatty liver disease

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• Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.

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• Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease*

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• ApoCIII gene variants modulate postprandial response to both glucose and fat tolerance tests.

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• Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E.

  1997cited by this paper
• Acute Effects of Insulin in the Control of VLDL Production in Humans: Implications for the insulin-resistant state

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• Insulin regulation of triacylglycerol-rich lipoprotein synthesis and secretion.

  1994cited by this paper
• Overexpression of human apolipoprotein C-III in transgenic mice results in an accumulation of apolipoprotein B48 remnants that is corrected by excess apolipoprotein E.

  1994cited by this paper
• Hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene are neither insulin resistant nor hyperinsulinemic.

  1994cited by this paper
• Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

  1992cited by this paper
• Insulin inhibits apolipoprotein B secretion in isolated human hepatocytes.

  1991cited by this paper
• Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice.

  1990cited by this paper
• A rapid method of total lipid extraction and purification.

  1959cited by this paper

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