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J Hepatol. 2017 Oct;67(4):809-817. doi: 10.1016/j.jhep.2017.06.008. Epub 2017 Jun 21.

Human germline hedgehog pathway mutations predispose to fatty liver.

Author information

1
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
2
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
3
Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC, United States.
4
Laboratory of Pathology, National Cancer Institute, Bethesda, MD, United States.
5
GlobalVet Pathology, Montgomery Village, MD, United States.
6
Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, United States; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, United States; Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC, United States.
7
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States; Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA, United States; Department of Pediatrics, Inova Children's Hospital and Virginia Commonwealth University School of Medicine, Falls Church, VA, United States; GeneDx, Gaithersburg, MD, United States.
8
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States. Electronic address: mamuenke@mail.nih.gov.

Abstract

BACKGROUND & AIMS:

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.

METHODS:

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.

RESULTS:

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 PPARγ, 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.

CONCLUSIONS:

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.

KEYWORDS:

Cirrhosis; GLI2; HPE; Hedgehog; Hepatocellular carcinoma; Holoprosencephaly; Liver fibrosis; Metabolic disease; NAFLD; NASH; Non-alcoholic fatty liver disease; SHH

PMID:
28645738
PMCID:
PMC5613974
DOI:
10.1016/j.jhep.2017.06.008
[Indexed for MEDLINE]
Free PMC Article

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