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Biology subjects

Brady, G. F.

Publications and source records attributed to Brady, G. F..

2 recordsLinked to original sources
bioRxiv2026

The inner nuclear membrane protein SUN1 regulates cullin-3 neddylation to maintain insulin signaling

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease and strongly linked to obesity and insulin resistance. We previously reported that the common nuclear envelope variant rs6461378 (g.842031C>T; SUN1 H118Y) associated with MASLD and related traits including insulin resistance. To gain insight into how wild-type (WT) and H118Y SUN1 might differentially impact insulin signaling, we performed affinity purification-mass spectrometry (AP-MS) in human liver-derived cells stably expressing WT or H118Y SUN1. Unbiased AP-MS revealed a novel SUN1-CUL3 interaction, with comparative analysis showing that WT SUN1 interacted robustly with CUL3, while CUL3 interaction was markedly diminished with H118Y SUN1. Cells in which SUN1 was silenced via siRNA, or in which H118Y SUN1 was ectopically expressed, showed increased CUL3 neddylation, which is required for cullin RING ligase (CRL)-mediated ubiquitination of insulin receptor substrate (IRS) proteins. Inhibition of neddylation restored IRS-1 levels and insulin signaling in H118Y SUN1-expressing cells. Together, our findings provide a potential mechanism of H118Y SUN1-driven insulin resistance and a viable therapeutic approach for its reversal.

physiology↗
bioRxiv2022

Hepatocyte-specific loss of LAP2α reduces hepatic steatosis in male mice by enhancing LMNA-mediated transcriptional regulation

There is increasing evidence for the importance of the nuclear envelope in lipid metabolism, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Human mutations in LMNA, encoding A-type nuclear lamins, cause early-onset insulin resistance and NASH, while hepatocyte-specific deletion of Lmna predisposes to NASH with fibrosis in male mice. Given that variants in the gene encoding LAP2, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2 in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2a-knockout (Lap2({Delta}Hep)) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 weeks or 6 months. In contrast to what was observed with hepatocyte-specific Lmna deletion, male Lap2a({Delta}Hep) mice showed no increase in hepatic steatosis or NASH compared to controls. Rather, Lap2a({Delta}Hep) mice demonstrated reduced hepatic steatosis, particularly after long-term HFD, with decreased susceptibility to diet-induced NASH. Accordingly, whereas pro-steatotic genes Cidea, Mogat1, and Cd36 were upregulated in Lmn-KO mice, they were downregulated in Lap2({Delta}Hep) mice, and there was a trend toward decreases in pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2a deletion protects against hepatic steatosis and NASH in mice; therefore, LAP2 might represent a potential therapeutic target in human NASH. Brief SummaryLoss of LAP2 in mouse hepatocytes protected against diet-induced hepatic steatosis and NASH.

physiology↗