Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.
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 kappa B-dependent tumor necrosis factor alpha 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.
Feldstein
Ariel E
AE
Department of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Werneburg
Nathan W
NW
Canbay
Ali
A
Guicciardi
Maria Eugenia
ME
Bronk
Steven F
SF
Rydzewski
Robert
R
Burgart
Laurence J
LJ
Gores
Gregory J
GJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004338:Drug Combinations; D005230:Fatty Acids, Nonesterified / Q000502:physiology*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019301:Oleic Acid / Q000506:poisoning*; D010168:Palmitates / Q000506:poisoning*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D012720:Severity of Illness Index; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D015703:Antigens, CD; C494826:BAX protein, human; C494827:Bax protein, mouse; D004338:Drug Combinations; D005230:Fatty Acids, Nonesterified; D016328:NF-kappa B; D010168:Palmitates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D019301:Oleic Acid; D002401:Cathepsin B