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Lipotoxcity
when tissues overeat
Emily Tieu
Xiaoqing Zhang


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What is lipotoxicity?

Excess calories stored as fat
Lipid accumulation in non-adipose
tissues
Results in cellular dysfunction and death
Affects kidneys, liver, heart, skeletal
muscle
Affects 25% of adult American
population

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Mechanism
FAs can be converted
to lipid intermediates
DAG, ceramides, fatty
acyl-CoAs
Impair cellular function
Mechanism for causing
cell dysfunction and
death not understood
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Cause
Genetics
Obesity
Protective effect?
Risk factor?
High fat diets
Leptin resistance
Leptin increases beta-oxidation and decreases
lipogenesis in non-adipocytes
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Pathophysiology
Heart
lipid accumulation that results from mismatch between lipid import and
utilization in the heart can lead to systolic ventricular dysfunction
Skeletal muscle
Changes in signaling pathways downstream of the insulin receptor are
most closely associated with accumulation of intracellular fatty acyl-CoA
and diacylglycerol
Pancreas
Lipid overload in pancreatic b-cells leads to dysregulated insulin
secretion with short-term increases and chronic decreases
Liver
In humans, triglyceride and FFA accumulation in the liver is
associated with non-alcoholic steatohepatitis (NASH)
kidney
FFAs carried by filtered albumin in the setting of proteinuria play a
role in the genesis of tubulointerstitial injury.
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limiting or preventing
lipotoxicity
Decrease overall the lipid
content of nonadipose
tissues
Divesion of excess lipid
away from non-adipose
tissues or celluar pathway
Target signaling or
metabolic pathways that
are critical for FFA-
induced cell dysfunction
or cell death.
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Still unknown
Genetic cause?
Obesity VS Lipotoxicity?
Mechanisms leading to cell death?
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References
Wende, Adam (March 2010). "Lipotoxicity in the Heart". Biochimica et
Biophysica Acta 1801 (3): 311319.
Unger, Roger. Lipotoxicity of Beta-Cells in Obesity and in Other Causes of
Fatty Acid Spillover. Diabetes February 2001 vol. 50 no. suppl 1 S118
Zuniga-Guajardo S, Zinman B. The metabolic response to the euglycemic
insulin clamp in type I diabetes and normal humans.
Metabolism1985;34:926930.
Stump DD, Fan X, Berk PD. Oleic acid uptake and binding by rat
adipocytesndefine dual pathways for cellular fatty acid uptake. J Lipid Res
2001; 42:509520.
Garg A, Misra A. Hepatic steatosis, insulin resistance, and adipose tissue
disorders. J Clin Endocrin Met 2002; 87:30193022.
Zhou YP, Grill V. Long term exposure to fatty acids and ketones inhibits b-
cell functions in human pancreatic islets of langerhans. J Clin Endocrinol
Metab 1995; 80:15841590.