Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

Meric Erikci Ertunc; Gökhan S. Hotamisligil

doi:10.1194/jlr.R066514

Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T. H. Chan School of Public Health, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA 02115

↵2To whom correspondence should be addressed. e-mail: ghotamis{at}hsph.harvard.edu

Abstract

Lipids encompass a wide variety of molecules such as fatty acids, sterols, phospholipids, and triglycerides. These molecules represent a highly efficient energy resource and can act as structural elements of membranes or as signaling molecules that regulate metabolic homeostasis through many mechanisms. Cells possess an integrated set of response systems to adapt to stresses such as those imposed by nutrient fluctuations during feeding-fasting cycles. While lipids are pivotal for these homeostatic processes, they can also contribute to detrimental metabolic outcomes. When metabolic stress becomes chronic and adaptive mechanisms are overwhelmed, as occurs during prolonged nutrient excess or obesity, lipid influx can exceed the adipose tissue storage capacity and result in accumulation of harmful lipid species at ectopic sites such as liver and muscle. As lipid metabolism and immune responses are highly integrated, accumulation of harmful lipids or generation of signaling intermediates can interfere with immune regulation in multiple tissues, causing a vicious cycle of immune-metabolic dysregulation. In this review, we summarize the role of lipotoxicity in metaflammation at the molecular and tissue level, describe the significance of anti-inflammatory lipids in metabolic homeostasis, and discuss the potential of therapeutic approaches targeting pathways at the intersection of lipid metabolism and immune function.

Footnotes

↵1 Present address of M. Erikci Ertunc: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037.
Abbreviations:

AP-1

activator protein 1

Arg2^−/−

arginase 2-deficient

ATGL

adipose triglyceride lipase

BAT

brown adipose tissue

DAG

diacylglycerol

ER

endoplasmic reticulum

FAHFA

fatty acid hydroxy fatty acid

FXR

farnesoid X receptor

GPR120

G protein-coupled receptor 120

iNKT

invariant natural killer T

iNOS

induced nitric oxide synthase (iNOS)

LD

lipid droplet

LXR

liver X receptor

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NKT

natural killer T

PKC

protein kinase C

PKR

protein kinase R

ROS

reactive oxygen species

snoRNA

small nucleolar RNA

TLR4

toll-like receptor 4

TUDCA

tauroursodeoxycholic acid
This work was supported in part by the Office of Extramural Research, National Institutes of Health Grants RO1DK052539, RO1HL125753, and RO1AI116901, a research grant from the Juvenile Diabetes Research Foundation, and sponsored research agreements from Union Chimique Belge (UCB), and Servier. M.E.E. is supported by a Catharina Foundation Postdoctoral Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.