Fatty liver disease is associated with metabolic syndrome, increased risk of type 2 diabetes (T2D), and other metabolic complications. There has been little progress in treatments for fat-induced liver failure and further studies are required for clarification of mechanisms. Mitochondrial dysfunction has been implicated in insulin resistance and is associated with hepatic fat accumulation and T2D. Studies in C. Elegans have shown that UBL-5 is involved in the activation of the mitochondrial unfolded protein response (UPRmt). This pathway upregulates mitochondrial proteases and chaperone proteins to alleviate proteostatic stress. To further explore the role of UBL-5 in the mammalian UPRmt, we generated a tamoxifen-inducible, liver-specific UBL-5 knockout mouse. Liver-specific deletion of UBL-5 in adult mice caused increased plasma hepatic enzymes, gross steatosis and death within 12 days following tamoxifen-induction. Histological examination of the liver revealed severe and diffuse multifocal hepatocellular necrosis, vacuolation, inflammation, lipid accumulation, and apoptosis. Most UPRmt genes (CHOP, ClpP, ClpX, Lonp1, HSP10, HSP70, ATF-5) were downregulated while mtHSP70 was upregulated. PGC1a mitochondrial biogenesis gene was downregulated. Interestingly, angiotensin-converting enzyme 2 (ACE2) expression was also reduced in KO livers. Mice were then treated with pioglitazone, or an ACE2-containing virus to determine if such treatments provide benefit. ACE2 expression was increased with both ACE2 virus and pioglitazone treatment. Liver enzymes showed significant improvement after treatment with both pioglitazone and ACE2.

In conclusion, we have generated a model that develops severe fatty liver disease and have shown that both genetic and pharmacological therapies may diminish this disease process. This study provides the first evidence for a critical role for UBL-5 in hepatic function.


V. Ntouma: None. C. Haralambous: None.

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