Mechanisms of lipotoxicity in NAFLD and clinical implications

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

With the epidemic of childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in pediatrics. NAFLD is strongly associated with insulin resistance and increased level of serum free fatty acids (FFAs). FFAs have direct hepatotoxicity through the induction of an endoplasmic reticulum stress response and subsequently activation of the mitochondrial pathway of cell death. FFAs may also result in lysosomal dysfunction and alter death receptor gene expression. Lipoapoptosis is a key pathogenic process in NAFLD, and correlates with progressive inflammation, and fibrosis. Accumulation of triglyceride in the liver results from uptake and esterification of FFAs by the hepatocyte, and is less likely to be hepatotoxic per se. To date, there are no proven effective therapies that halt NAFLD progression or unfortunately improve prognosis in children. The cellular mechanisms of lipotoxicity are complex but provide potential therapeutic targets for NAFLD. In this review we discuss several potential therapeutic opportunities in detail including inhibition of apoptosis, c-Jun-N-terminal kinase, and endoplasmic reticulum stress pathways.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalJournal of Pediatric Gastroenterology and Nutrition
Volume53
Issue number2
DOIs
StatePublished - Aug 2011

Fingerprint

Nonesterified Fatty Acids
Endoplasmic Reticulum Stress
Death Domain Receptors
JNK Mitogen-Activated Protein Kinases
Esterification
Pediatric Obesity
Disease Progression
Insulin Resistance
Liver Diseases
Hepatocytes
Triglycerides
Fibrosis
Chronic Disease
Cell Death
Therapeutics
Non-alcoholic Fatty Liver Disease
Pediatrics
Apoptosis
Inflammation
Gene Expression

Keywords

  • Bcl-2 homology 3-only protein
  • c-Jun-N-terminal kinase
  • C/EBP-homologous protein (CHOP)
  • endoplasmic reticulum stress
  • free fatty acids
  • nonalcoholic fatty liver disease
  • nonalcoholic steatohepatitis

ASJC Scopus subject areas

  • Gastroenterology
  • Pediatrics, Perinatology, and Child Health

Cite this

Mechanisms of lipotoxicity in NAFLD and clinical implications. / Ibrahim, Samar C; Kohli, Rohit; Gores, Gregory James.

In: Journal of Pediatric Gastroenterology and Nutrition, Vol. 53, No. 2, 08.2011, p. 131-140.

Research output: Contribution to journalArticle

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