NDLI: The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Li, ZhengZheng Berk, Michael McIntyre, Thomas M. Gores, Gregory J. Feldstein, Ariel E.
Description	Country affiliation: United States Author Affiliation: Li Z ( Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195, USA.)
Abstract	UNLABELLED: Impaired mitochondrial function is largely thought to be a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms resulting in mitochondrial dysfunction in NAFLD remain poorly understood. This study examined the effects of excessive accumulation of free fatty acids (FFAs) in liver cells on mitochondrial function and the role of the lysosomal-mitochondrial axis on lipotoxicity. Primary mouse hepatocytes, HepG2 and McNtcp.24 cells, were treated with varied concentrations of FFAs with different degrees of saturation for up to 24 hours. Mitochondrial function was monitored by real-time imaging, cytochrome c redistribution, and reactive oxygen species (ROS) production. The temporal relationship of lysosomal and mitochondrial permeabilization was established. Activity of the lysosomal protease cathepsin B was suppressed by genetic and pharmacological approaches. Cathepsin B-knockout mice and wild-type animals were place on a high-carbohydrate diet for 16 weeks, and mitochondrial function and liver damage were assessed. Exposure of liver cells to saturated FFAs resulted in mitochondrial depolarization, cytochrome c release, and increased ROS production. Lysosomal permeabilization and cathepsin B redistribution into the cytoplasm occurred several hours prior to mitochondrial dysfunction. Either pharmacological or genetic inhibition of cathepsin B preserved mitochondrial function. Finally, cathepsin B inactivation protected mitochondria, decreased oxidative stress, and attenuated hepatic injury in vivo. CONCLUSION: These data strongly suggest excessive accumulation of saturated FFAs in liver cells directly induce mitochondrial dysfunction and oxidative stress. Our data further suggest this process is dependent on lysosomal disruption and activation of cathepsin B.
File Format	HTM / HTML
ISSN	02709139
e-ISSN	15273350
DOI	10.1002/hep.22183
Journal	Hepatology
Issue Number	5
Volume Number	47
Language	English
Publisher	Wiley
Publisher Date	2008-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Hepatology Fatty Acids, Nonesterified Toxicity Fatty Liver Metabolism Lysosomes Mitochondria, Liver Animals Cathepsin B Disease Models, Animal Epidemiology Mice Mice, Inbred C57bl Permeability Rna, Small Interfering Genetics Reactive Oxygen Species Transfection Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Hepatology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation.

Bax inhibition protects against free fatty acid-induced lysosomal permeabilization.

Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.

Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels.

The Lysosomal-Mitochondrial Axis in Free Fatty Acid–Induced Hepatic Lipotoxicity

Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids.

Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models.

IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice.

Protective effects of the antioxidant 4b,5,9b,10-tetrahydroindeno[1,2-b]indole against TCDD toxicity in C57BL/6J mice.

The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity.

Similar Documents

Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation.

Bax inhibition protects against free fatty acid-induced lysosomal permeabilization.

Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.

Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels.

The Lysosomal-Mitochondrial Axis in Free Fatty Acid–Induced Hepatic Lipotoxicity

Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids.

Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models.

IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice.

Protective effects of the antioxidant 4b,5,9b,10-tetrahydroindeno[1,2-b]indole against TCDD toxicity in C57BL/6J mice.

The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity.