Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway

Ariel E. Feldstein, Nathan W. Werneburg, Ali Canbay, Maria Eugenia Guicciardi, Steven F. Bronk, Robert Rydzewski, Laurence J. Burgart, Gregory James Gores

Research output: Contribution to journalArticle

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a serious health problem. Although NAFLD represents a form of lipotoxicity, its pathogenesis remains poorly understood. The aim of this study was to examine the cellular mechanisms involved in free fatty acid (FFA)-mediated hepatic lipotoxicity. FFA treatment of liver cells resulted in Bax translocation to lysosomes and lysosomal destabilization with release of cathepsin B (ctsb), a lysosomal cysteine protease, into the cytosol. This process was also partially dependent on ctsb. Lysosomal destabilization resulted in nuclear factor κB-dependent tumor necrosis factor α expression. Release of ctsb into the cytoplasm was also observed in humans with NAFLD and correlated with disease severity. In a dietary murine model of NAFLD, either genetic or pharmacological inactivation of ctsb protected against development of hepatic steatosis, liver injury, and insulin resistance with its associated "dysmetabolic syndrome." In conclusion, these data support a lipotoxic model of FFA-mediated lysosomal destabilization.

Original languageEnglish (US)
Pages (from-to)185-194
Number of pages10
JournalHepatology
Volume40
Issue number1
DOIs
StatePublished - Jul 2004

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Cathepsin B
Nonesterified Fatty Acids
Liver
Cysteine Proteases
Fatty Liver
Lysosomes
Cytosol
Insulin Resistance
Cytoplasm
Tumor Necrosis Factor-alpha
Pharmacology
Non-alcoholic Fatty Liver Disease
Health
Wounds and Injuries
Therapeutics

ASJC Scopus subject areas

  • Hepatology

Cite this

Feldstein, A. E., Werneburg, N. W., Canbay, A., Guicciardi, M. E., Bronk, S. F., Rydzewski, R., ... Gores, G. J. (2004). Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway. Hepatology, 40(1), 185-194. https://doi.org/10.1002/hep.20283

Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway. / Feldstein, Ariel E.; Werneburg, Nathan W.; Canbay, Ali; Guicciardi, Maria Eugenia; Bronk, Steven F.; Rydzewski, Robert; Burgart, Laurence J.; Gores, Gregory James.

In: Hepatology, Vol. 40, No. 1, 07.2004, p. 185-194.

Research output: Contribution to journalArticle

Feldstein, AE, Werneburg, NW, Canbay, A, Guicciardi, ME, Bronk, SF, Rydzewski, R, Burgart, LJ & Gores, GJ 2004, 'Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway', Hepatology, vol. 40, no. 1, pp. 185-194. https://doi.org/10.1002/hep.20283
Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway. Hepatology. 2004 Jul;40(1):185-194. https://doi.org/10.1002/hep.20283
Feldstein, Ariel E. ; Werneburg, Nathan W. ; Canbay, Ali ; Guicciardi, Maria Eugenia ; Bronk, Steven F. ; Rydzewski, Robert ; Burgart, Laurence J. ; Gores, Gregory James. / Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway. In: Hepatology. 2004 ; Vol. 40, No. 1. pp. 185-194.
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