Analysis of fatty liver disease development and progression in a combined mouse model of hedgehog signaling attenuation and diet-induced hepatic steatosis

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease and a leading cause of liver transplantation in the United Sates. Hedgehog (Hh) signaling has been implicated in liver lipid metabolism and the early stages of NAFLD; however, its precise role remains unclear. We examined the prevalence of NAFLD in patients with overt or microform holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Hh signaling. To test the hypothesis that Hh signaling attenuation predisposes to liver steatosis, we subjected Gli2 heterozygous null (Gli2+/-) mice to two unique dietary models of fatty liver. Compared to the general population, the prevalence of NAFLD was significantly higher in the HPE cohort independent of obesity, especially among younger individuals. Gli2 heterozygosity caused increased weight gain and liver steatosis on a high fat diet, and increased liver steatosis in the absence of weight gain on a methionine and choline deficient diet. Increased liver steatosis in Gli2+/- mice 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. In addition, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/- mice. Our results indicate that germline mutations affecting Hh signaling predispose to NAFLD with reduced or absent fibrosis, and might increase the risk of hepatocellular carcinoma.

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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