Journal
JOURNAL OF HEPATOLOGY
Volume 67, Issue 4, Pages 809-817Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2017.06.008
Keywords
Non-alcoholic fatty liver disease; NAFLD; Metabolic disease; Hedgehog; SHH; GLI2; NASH; Liver fibrosis; Cirrhosis; Hepatocellular carcinoma; Holoprosencephaly; HPE
Categories
Funding
- Division of Intramural Research, National Human Genome Research Institute
- National Institute on Alcohol Abuse and Alcoholism [P60-AA011605]
- National Institute of Dental and Craniofacial Research grant [K99DE022101]
Ask authors/readers for more resources
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 PPAR gamma, 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 the activation of 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. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available