Briand, F. | Search bioRxiv

bioRxiv2020

The hepatic compensatory response to elevated systemic sulfide impairs medium chain fat oxidation and promotes diabetes

Impaired hepatic glucose and lipid metabolism are hallmarks of type-2 diabetes. Increased sulfide production from cysteine, or sulfide-donor compounds, may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver-enriched mitochondrial SOP enzyme thiosulfate sulfur-transferase (Tst-/- mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia and fatty liver, despite whole-body insulin-sensitisation. Unexpectedly, hepatic sulfide levels were normal in Tst-/- mice, a result of homeostatic induction of mitochondrial sulfide disposal and glutathione excretion associated with net suppression of protein persulfidation and nuclear respiratory factor-2 target proteins. Proteomic and persulfidomic profiling converged on gluconeogenesis and hepatic lipid metabolism and revealed a selective deficit in medium-chain fatty acid oxidation in Tst-/- mice. We reveal a critical role for TST in hepatic metabolism that raises implications for sulfide-donor strategies in the context of liver function and metabolic disease.

physiology↗

bioRxiv2019

Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of non-alcoholic steatohepatitis

AimNon-alcoholic steatohepatitis (NASH) is an emerging health problem worldwide. However, efficacious pharmacological treatment for NASH is lacking. A major issue for preclinical evaluation of potential therapeutics for NASH is the limited number of appropriate animal models, i.e., models that do not require long-term dietary intervention and adequately mimic disease progression in humans. The present study aimed to evaluate a 3-week dietary mouse model of NASH and to validate it by studying the effects of liraglutide, a compound in advanced clinical development for NASH.\n\nMethodsC57BL6/J mice were fed a diet high in fat (60%), cholesterol (1.25%) and cholic acid (0.5%) along with 2% hydroxypropyl-{beta}-cyclodextrin in drinking water (HFCC-CDX diet). Histological and biological parameters were measured at 1 and 3 weeks. Following 1-week diet induction, liraglutide was administrated daily for 2 weeks, and then NASH-associated phenotypic aspects were evaluated in comparison with control mice.\n\nResultsPrior to treatment with liraglutide, mice fed the HFCC-CDX diet for 1 week developed liver steatosis and had increased levels of oxidative-stress markers and hepatic and systemic inflammation. For mice not treated with liraglutide, these aspects were even more pronounced after 3 weeks of the dietary period, with additional liver insulin resistance and fibrosis. Liraglutide treatment corrected the diet-induced alterations in glucose metabolism and significantly reduced hepatic steatosis and inflammation.\n\nConclusionThis study provides a novel 3-week dietary model of mice that rapidly develop NASH features, and this model will be suitable for evaluating the therapeutic efficacy of compounds in preclinical drug development for NASH.

pathology↗