Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Liver fat accumulation correlates with the metabolic syndrome, increases risk of type 2 diabetes (T2D), advanced liver disease & other metabolic complications. There are no simple/widely effective solutions for fat-induced liver failure & further studies are required for clarification of mechanisms. Mitochondrial dysfunction has been implicated in insulin resistance & is associated with hepatic fat accumulation & T2D. Subsequently it has been shown in C. Elegans that UBL-5 is involved in mitochondrial unfolded response (UPRmt) to ensure chaperone proteins are transcribed & available to relieve stress. To explore the role of UBL-5 in UPRmt, we generated inducible & liver-specific UBL-5 KO mice. 

Liver-specific deletion of UBL-5 caused gross steatosis, increased hepatic enzymes indicating liver failure (Table 1). Death occurred within 12 days following induction. CHOP & UPRmt genes were downregulated while mtHSP70 was upregulated. PGC1a gene (inducer of mitochondrial biogenesis) was reduced in UBL-5 KO mice. Interestingly, angiotensin-converting enzyme 2 (ACE2) expression was also reduced in KO livers. Mice were then treated with the thiazolidinedione pioglitazone, or an ACE2-containing virus to determine if such treatments provide benefit.  ACE2 expression was increased with both ACE2 virus & pioglitazone treatment.  Liver enzymes showed significant improvement after treatment with both pioglitazone & ACE2 (Table1). Furthermore, CHOP expression was normalized with pioglitazone treatment.

Table 1: Liver enzymes.

In conclusion, we have generated a model that develops severe fatty liver disease & have shown that both genetic & pharmacological therapies may diminish this disease process.