Human germline hedgehog pathway mutations predispose to fatty liver.
Authors Guillen-Sacoto MJ, Martinez AF, Abe Y, Kruszka P, Weiss K, Everson JL, Bataller
R, Kleiner DE, Ward JM, Sulik KK, Lipinski RJ, Solomon BD, Muenke M
Submitted By Submitted Externally on 9/29/2017
Status Published
Journal Journal of hepatology
Year 2017
Date Published 10/1/2017
Volume : Pages 67 : 809 - 817
PubMed Reference 28645738
Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver
disease. Activation of hedgehog (Hh) signaling has been implicated in the
progression of NAFLD and proposed as a therapeutic target; however, the effects
of Hh signaling inhibition have not been studied in humans with germline
mutations that affect this pathway., Patients with holoprosencephaly (HPE), a
disorder associated with germline mutations disrupting Sonic hedgehog (SHH)
signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh
signaling attenuation (Gli2 heterozygous null: Gli2(+/-)) and diet-induced NAFLD
was used to examine aspects of NAFLD and hepatic gene expression profiles,
including molecular markers of hepatic fibrosis and inflammation., Patients with
HPE had a higher prevalence of liver steatosis compared to the general
population, independent of obesity. Exposure of Gli2(+/-) mice to fatty
liver-inducing diets resulted in increased liver steatosis compared to wild-type
mice. Similar to humans, this effect was independent of obesity in the mutant
mice and was associated with decreased expression of pro-fibrotic and
pro-inflammatory genes, and increased expression of PPAR?, a potent
anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor
suppressors p53 and p16INK4 were found to be downregulated in the Gli2(+/-) mice
exposed to a high-fat diet., Our results indicate that germline mutations
disrupting Hh signaling promotes liver steatosis, independent of obesity, with
reduced fibrosis. While Hh signaling inhibition has been associated with a
better NAFLD prognosis, further studies are required to evaluate the long-term
effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty
liver disease (NAFLD) is characterized by excess fat deposition in the liver
predominantly due to high calorie intake and a sedentary lifestyle. NAFLD
progression is usually accompanied by activation of the Sonic hedgehog (SHH)
pathway leading to fibrous buildup (scar tissue) and inflammation of the liver
tissue. For the first time patients with holoprosencephaly, a disease caused by
SHH signaling mutations, are shown to have increased liver steatosis independent
of obesity. This observation was recapitulated in a mouse model of attenuated
SHH signaling that also showed increased liver steatosis but with decreased
fibrosis and inflammation. While SHH inhibition is associated with a good NAFLD
prognosis, this increase in liver fat accumulation in the context of SHH
signaling inhibition must be studied prospectively to evaluate its long-term
effects, especially in individuals with Western-type dietary habits.

StrainDevelopment StatusCreation MethodOptions
B6.Cg-Gli2tmMatPhenotyping ongoingknockout

Gli2GLI-Kruppel family member GLI2