Gene expression profiles of livers from male LMNA+/+, LMNA flx/+, and LMNA flx/flx; Alb-Cre+ C57BL/6 mice fed normal chow or high fat diet. Mus musculus

To investigate the molecular basis for male-specific steatohepatitis in Lamin A/C-deficient livers, microarray gene expression analysis was performed on total liver RNA isolated from 26- to 39-week-old, male LMNA+/+, LMNA flx/+, and LMNA flx/flx; Alb-Cre+ C57BL/6 mice fed either normal chow (NC) or high fat diet plus carbohydrate-supplemented water (HFD). Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina in metazoan cells. Mutations in LMNA, which encodes lamins A/C, cause diseases termed laminopathies, including lipodystrophy, cardiomyopathy, and premature aging. The lamin A/C mutation-associated Dunnigan familial partial lipodystrophy is typically accompanied by fatty liver disease. The role of lamins in the liver is unknown, and it is unclear whether laminopathy-associated liver disease is due to primary hepatocyte defects or systemic alterations. To address these questions, mice carrying a hepatocyte-specific deletion of Lmna (KO mice) were generated. KO hepatocytes manifested abnormal nuclear morphology, and KO mice developed spontaneous male-selective hepatosteatosis, with increased susceptibility to high fat diet-induced steatohepatitis and fibrosis. The molecular mechanism by which liver-specific Lamin A/C deficiency induces male-specific steatohepatitis is unknown. The microarray data presented here demonstrates that hepatic Lmna deficiency is associated with upregulated expression of fatty acid transporters, lipid biosynthetic enzymes, lipid-droplet associated proteins, and interferon-regulated genes and other pro-inflammatory mediators. Overall design: Global gene expression profiling of liver RNA isolated from 26- to 39-week-old LMNA+/+, LMNA flx/+, and LMNA flx/flx; Alb-Cre+ C57BL/6 mice fed either normal chow (NC) or high fat diet plus carbohydrate-supplemented water (HFD). The following mouse livers were used in gene expression profiling: LMNA+/+; Alb-Cre+, NC-fed (n=2); LMNA flx/+; Alb-Cre+, NC-fed (n=3); LMNA flx/flx; Alb-Cre+, NC-fed (n=3); LMNA flx/+; Alb-Cre+, HFD-fed (n=3); and LMNA flx/flx; Alb-Cre+, HFD-fed (n=3).