Human germline hedgehog pathway mutations predispose to fatty liver

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 affecting 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 high-fat diet. Conclusions Our results indicate that germline mutations disrupting Hh signaling promote 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.

Signaling in Simple Steatosis and Non-alcoholic Steatohepatitis Cirrhosis: TGF-β1, YAP/TAZ, and Hedgehog Pathway Activity

“…On the other hand, it is observed that the prevalence of steatosis increases in patients with a defect in the SHH pathway. This finding is confirmed by animal studies as well (16). In addition, the mutation in the mouse liver Gli2 protein (one of the mediators of HH pathway that plays a role in expressing various genes and its mutation leads to the impairment of HH pathway), and then its exposure to high-fat diet causes reduced inflammation and fibrosis.…”

Hedgehog signalling in liver pathophysiology

“…Hh ligands have been demonstrated in human lipoproteins 45 but the source(s) of lipoprotein-associated Hh ligands and their function in man are unknown. This issue merits further study given recent evidence that inherited Smoothened defects which abrogate Hh signaling in humans lead to hepatic steatosis 46 .…”

“…This enrichment appears to be independent of obesity and seems to be driven predominately by the fact that reduced Smo function associates with hepatic steatosis. Indeed, expression of proinflammatory and profibrotic genes is generally low in such patients 46 . Similarly, genetically modified mice with reduced Hh pathway activity caused by global haploinsufficiency of Gli-2 develop more steatosis but less inflammation than wild type mice when exposed to steatogenic diets 46 .…”

“…Indeed, expression of proinflammatory and profibrotic genes is generally low in such patients 46 . Similarly, genetically modified mice with reduced Hh pathway activity caused by global haploinsufficiency of Gli-2 develop more steatosis but less inflammation than wild type mice when exposed to steatogenic diets 46 . These findings in the livers of humans and mice with genetic inhibition of the Hh pathway are consistent with earlier publications proving that genetic activation of the Hh pathway directly inhibits lipogenesis in flies and mammals 22,44 , as well as more recent papers showing that targeted genetic/pharmacological activation of Hh signaling reverses steatosis in fatty hepatocytes harvested from obesity-related mice models of NAFLD 42 .…”

Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis

“…Our results that Smo deletion is responsible for lipid accumulation are corroborated by another recent study, where patients with holoprosencephaly, a disease caused by genetic or teratogenic disruption of Hh signaling, and mice heterozygous for Gli2 deletion were found to develop liver steatosis. 38 In contrast, a recent study of Kwon and colleagues demonstrated that Smo-KO did not affect lipid accumulation in normal chow fed SmoLKO mice. The reason for this discrepancy could be that Kwon et al measured triglycerides in whole liver material with a less sensitive detection method.…”