Cholesterol and Sphingolipids in Non-Alcoholic fatty liver disease . José C. Fernández-Checa Liver Unit, Hospital Clinic CIBEK and IDIBAPS Instituto Investigaciones Biomédicas Barcelona Consejo Superior Investigaciones Científicas Barcelona, Spain ICDM 2013 & 5 AASD Seoul, Nov 7 2013 th
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Cholesterol and Sphingolipids in Non-Alcoholic
fatty liver disease .
José C. Fernández-Checa
Liver Unit, Hospital Clinic
CIBEK and IDIBAPS
Instituto Investigaciones Biomédicas Barcelona
Consejo Superior Investigaciones Científicas
Barcelona, Spain
ICDM 2013
& 5 AASD
Seoul, Nov 7 2013
th
NAFLD
NASH Cirrhosis/HC
ALD
Steatosis
ASH
Steatohepatitis
FATTY LIVER DISEASE
Inflammation
Hepatocellular death
Oxidative stress
Fibrosis
?
Mechanisms involved in ALD/NAFLD
Alcohol Obesity
ALD NAFLD
ER stress Mitochondrial
dysfunction
Methionine metab Insulin resistance
NASH: mitochondrial disease
AcetaldehydeType 2 diabetes
Homocysteine
Disease progression
FFA
TGApoB +
TNFR1/R2
TNF
GSH
CH
CH
ER
TNFR1/R2
TNF
GSH
endosomes
Susceptibility to TNF/Fas?
ASH/NASH
Triglyceride/FFA loading Cholesterol loading
Mitochondrial Cholesterol in SteatohepatitisLombardi diet feeding
(choline deficient)
Ob/ob mice
2% cholesterol feeding (HC)
NPC1 knockout mice
Ob/ob mice2-14 days
FFA
TG
CH
*
* *
**
Oil-Red Filipin
Cholesterol loading sensitizes hepatocytes to TNF
Mari et al, Cell Metab, 2006
Mari et al, Cell Metab 2006
Mitochondrial free cholesterol loading increases membrane order and
depletes mGSH
Impact of free cholesterol in
human NASH?
Caballero, J Hepatol, 2009
Enhanced free cholesterol in human NASH.
Caballero, J Hepatol, 2009
StARD1, a mitochondrial cholesterol carrier, is overexpressed in human NASH.
#
.
#
FC
(µg/mg protein)11+/-3 13+/-4 52+/-6
Susceptibility to TNF/Fas
ASH/NASH
CH
CH
CH
CH
CH
CH
CH
GSH
GSH
2-OGC
CLCLOOH
StARD1
CH
CH
CH
CH
CH
CH
GSH
2-OGC
TNF/Fas
Susceptibility to TNF/Fas
ASH/NASH
CH
CH
CH
CH
CH
CH
CH
GSH
GSH
2-OGC
CLCLOOH
StARD1?
CH
CH
CH
CH
CH
CH
GSH
2-OGC
TNF/Fas
?
Mechanisms involved in ALD/NAFLD
Alcohol Obesity
ALD NAFLD
ER stress Mitochondrial
cholesterol loading
Methionine metab Insulin resistance
AcetaldehydeType 2 diabetes
Homocysteine
Disease progression
?
Tunicamycin-induced ER stress induces StARD1 expression which is prevented by
TUDCA
Fernandez et al, 2012
StARD1 SREBP-2
Thus, StARD1 is a novel target gene regulated by ER stress
PMH
+
Tm
Mechanisms involved in ALD/NAFLD
Alcohol Obesity
ALD NAFLD
ER stress Mitochondrial
dysfunction
Methionine metab Insulin resistance
AcetaldehydeType 2 diabetes
Homocysteine
Disease progression
Lipogenesis
Insulin resistanceOxidative stress
Cell death
mChol, mGSH
?
Serine+ Palmitoyl-CoA
SPT
3-ketoesphinganine
Sphinganine
Sphingosine
Dihydroceramide
ER (de novo synthesis)
CERAMIDE SphingomyelinASMase
Endosomes/lysosomes
Pro-apoptotic
Pro-fibrotic
Pro-NAFLD
Garcia-Ruiz et al, J. Clin. Invest. 2003
Mari et al, J. Clin. Invest. 2004
Mari et al, Cell Metab 2006
Mari et al, Gastroenterology 2008
Moles et al, Hepatology 2010
Moles et al, Am J. Pathol 2011
Moles et al, J. Biol. Chem 2012
Fernandez et al, J Hepatol 2013
Fucho et al, Sci Transl Med 2013
Baulies et al, In prep 2013
NSMase
Ceramide generation in cells
ASMase
EXPERIMENTAL DESIGN
ASMase-/- mice
HFD (60% cal)
MCD
ASMase+/+ mice
(WT mice)
HFD (60% cal)
+
Amitriptyline
1
2
CHOLESTEROL
FILIPIN
SPHINGOMYELIN
ASMase is required for HFD or MCD-induced macrosteatosis
Fucho et al, 2013
HFD MCD
ASMase
Steatosis
ASMase is required for HFD and MCD induced steatosis
HFD ER stress steatosis
ASMase ?
ASMase deficiency prevents HFD-induced ER stress
Fucho et al, 2013
ATF4 PDI Edem
But ASMase KO mice is sensitive to tunicamycin-induced ER stress and steatosis