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Diabetologia. 2011 Jun;54(6):1437-46. doi: 10.1007/s00125-011-2074-z. Epub 2011 Feb 24.

Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells.

Author information

1
Division of Metabolic Diseases, Center for Biomedical Sciences, National Institute of Health, 643 Yeonje-ri, Gangoe-myeon, Cheongwon-gun, Chungcheongbuk-do 363-951, South Korea.

Abstract

AIMS/HYPOTHESIS:

Lon protease degrades oxidatively damaged proteins in mitochondrial matrix. To examine the relationships between mitochondrial quality control, mitochondrial functions and diabetes, we investigated whether lon protease deficiency influences insulin resistance by affecting mitochondrial function.

METHODS:

Lon protease-specific small interfering RNA (siRNA) was transfected into human liver SK-HEP-1 cells and changes in molecules related to insulin resistance were analysed.

RESULTS:

Reduction in lon protease was achieved using specific siRNA-induced mitochondrial dysfunction in human liver SK-HEP-1 cells. Concurrently, insulin signalling and subsequent insulin action were impaired and levels of gluconeogenic enzymes were increased by lon protein deficiency. Moreover, the activity of mitogen-activated protein kinases and transcription factors related to hepatic gluconeogenesis were elevated in LON (also known as LONP1) siRNA-transfected cells via increased intracellular reactive oxygen species production. Overproduction of lon protease restored mitochondrial function and also diminished the insulin resistance induced by treatment with cholesterol and palmitate. In addition, levels of lon protease decreased dramatically in livers of diabetic db/db mice compared with their lean mice counterparts.

CONCLUSIONS/INTERPRETATION:

Here we have demonstrated that reduction of lon protease induced hepatic insulin resistance by lowering mitochondrial function. This is the first study to report that defects in mitochondrial protein quality control could cause insulin resistance and diabetes.

PMID:
21347624
DOI:
10.1007/s00125-011-2074-z
[Indexed for MEDLINE]

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