Role of ceramides in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with a histological spectrum ranging from steatosis alone, to nonalcoholic steatohepatitis (NASH). The latter is associated with an increased risk for progression to cirrhosis. Ceramides are a lipid species that exert biological effects through cellular proliferation, differentiation and cell death, and interact with several pathways involved in insulin resistance, oxidative stress, inflammation, and apoptosis, all of which are linked to NAFLD. Herein, we propose a mechanism through which ceramides contribute to the development of NAFLD and progression to NASH, due in part to second messenger effects via TNF-α. A better understanding of the role of ceramides in steatohepatitis has both diagnostic and therapeutic implications for the treatment of fatty liver disease.

Spinal Cord Injury Causes Chronic Liver Pathology in Rats

“…Because certain lipids-in particular ceramides-are important signaling molecules and inflammatory mediators in NASH, 44 quantitative lipidomics was used to examine changes in hepatic ceramides after thoracic SCI. The data reveal that ceramide precursors (dihydroxyceramides) and mature ceramides increased significantly in the liver over the first week post-injury.…”

“…46 In this way, vitamin E inhibits two pathways of ceramide synthesis and thereby may prevent ceramide elevation in the liver at 21 dpi despite increased SPT mRNA. Ceramide production is also induced by inflammatory cytokines, such as TNF-a and IL-1b, 44 both of which are increased after SCI and may contribute to ceramide formation through the induction of hydrolytic or recycling pathways, although this remains to be determined.…”

“…44 Ceramides also can elicit inflammation, 28,29 in part by stimulating Toll-like receptor-4 (TLR4), which is expressed by most cells in the liver. 48 In hepatocytes and Kupffer cells (hepatic macrophages), TLR4 activation in turn drives the production of ceramides, 49,50 which can then lead to more pathology as a feed-forward cascade is established.…”

“…54 Ceramides also contribute to metabolic syndrome because they attenuate insulin signaling in hepatocytes, macrophages, and muscle. 44,55 In addition to these local effects, ceramides are thought to circulate as lipoprotein complexes that may have CNS access, and could exacerbate intraspinal pathology after SCI, because ceramides impair energy metabolism, induce oxidative stress, and reduce viability in neurons. 31 Indeed, hepatic ceramides are thought to aggravate cognitive impairment and neurodegeneration in Alzheimer's disease and alcohol-mediated neurodegeneration.…”

Biomarkers of NAFLD progression: a lipidomics approach to an epidemic

“…Lipidomic analyses of human serum indicate that ether-linked phospholipids, certain neutral lipids, and FAs show suggestive differences between NASH and steatosis for some classes of patients by degree of obesity ( 15 ). Ceramides have been proposed to participate in the development and progression of NAFLD ( 16 ).…”