Human germline hedgehog pathway mutations predispose to fatty liver

Area of Science:

• Hepatology
• Genetics
• Molecular Biology

Background:

• Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver condition.
• Sonic hedgehog (SHH) signaling pathway activation is implicated in NAFLD progression and is a potential therapeutic target.
• The impact of SHH signaling inhibition in humans with germline mutations affecting this pathway remains unstudied.

Purpose of the Study:

• To investigate the association between germline mutations in the SHH signaling pathway and NAFLD.
• To examine the effects of SHH signaling attenuation on liver steatosis, fibrosis, and inflammation in a mouse model.

Main Methods:

• Clinical evaluation of patients with holoprosencephaly (HPE), a disorder of SHH signaling mutations, for NAFLD.
• Development and utilization of a Gli2 heterozygous null (Gli2+/-) mouse model with diet-induced NAFLD.
• Analysis of hepatic gene expression, including markers of fibrosis and inflammation.

Main Results:

• Patients with HPE exhibited a higher prevalence of liver steatosis, independent of obesity.
• Gli2+/- mice on a high-fat diet showed increased liver steatosis, independent of obesity, with reduced pro-fibrotic and pro-inflammatory gene expression.
• PPARγ expression was increased, while tumor suppressors p53 and p16INK4 were downregulated in Gli2+/- mice.

Conclusions:

• Germline mutations disrupting SHH signaling promote liver steatosis without increasing obesity-related fibrosis.
• While SHH inhibition may be linked to a better NAFLD prognosis, the long-term consequences of SHH pathway mutations require further investigation.