Lamin A/C acts maintains hepatocyte nuclear shape and protects male mice from steatohepatitis by regulating growth hormone signaling and reducing activity of STAT1, researchers report in the November issue of Cellular and Molecular Gastroenterology and Hepatology. These observations show how variants in genes encoding lamins affect risk for steatohepatitis and liver fibrosis.
Lamins are nuclear intermediate filament proteins that help form the nuclear lamina. Mutations in LMNA, which encodes lamin A/C, cause laminopathies such as muscular dystrophy, dilated cardiomyopathy, and Dunnigan-type familial partial lipodystrophy (FPLD2)
Hepatosteatosis occurs in many patients with FPLD2 and other lipodystrophies and can progress to steatohepatitis. However, it is not clear how lipodystrophy-associated mutations in lamin promote hepatic steatosis.
To characterize the functions of lamin A/C in the liver, Raymond Kwan et al generated mice with hepatocyte-specific deletion of Lmna.
They found that hepatocyte deficiency of lamin A/C induced spontaneous liver injury in male but not female mice. It also promoted hepatosteatosis in male mice placed on a high-fat diet, resulting in liver hypertrophy and nodularity and body mass decrease. There were no changes in serum triglycerides between LMNA knockout vs wild-type mice, regardless of diet.
Development of steatohepatitis associated with increased transcription of genes encoding fatty acid-binding proteins, lipogenic enzymes, and lipid transporters. The most highly up-regulated gene in livers of male, but not female, LMNA-knockout mice was Cidea, which encodes a lipid droplet–associated protein that promotes hepatic steatosis. Livers of LMNA-knockout mice also upregulated genes related to immunity and the interferon response and had increased infiltration by inflammatory cells. Consistent with findings from histology, livers from LMNA-knockout mice had increased expression of genes that regulate fibrosis.
Kwan et al wondered whether the male-specific effects of Lmna could be due to signaling via the growth hormone receptor, a sex-specific regulator of gene expression in hepatocytes.
The found that lamin A/C deficiency disrupted hepatic growth hormone receptor signaling in mouse hepatocytes. LMNA-knockout hepatocytes exposed to growth hormone had reduced activation of Janus kinase 2 (JAK2), mitogen-activated protein kinase 1 (ERK), and STAT5, compared to heptocytes with wild-type LMNA. The dysregulation of STAT5-dependent gene transcription increased expression and activation STAT1 and interferon-regulated genes (see figure).
Kwan et al conclude that lamins maintain hepatocyte homeostasis in a cell-autonomous manner and regulate hepatic growth hormone signaling. They state that development of steatohepatitis in only male LMNA-knockout mice is similar to sex differences reported in development of nonalcoholic fatty liver disease (NAFLD) and in some of the laminopathies. In the United States and China, there is a higher prevalence of NAFLD in men than in premenopausal women.
In an editorial that accompanies the article, Tim Hendrikx and Bernd Schnabl explain that hepatic steatosis has been associated with genetic variants in LMNA and is common in patients with FPLD2, along with other signs of metabolic syndrome. Patients with the LMNA variant rs57920071 were reported to have signs of hepatic steatosis.
Hendrikx and Schnabl propose that development of fatty liver in patients with FPLD2 might result from the effects of LMNA deficiency on hepatocytes reported by Kwan et al, rather than the effects of metabolic syndrome. Large genetic studies are required to determine the relevance of lamin polymorphisms inthe development of NAFLD and steatohepatitis, in male patients in particular.