Hepatocyte and adipocyte CDO1-mediated intracellular cysteine catabolism differentially modulates diet-induced obesity and fatty liver in mice.

Background and Aims: Plasma cysteine has been positively linked to BMI in humans. Consistently, dietary cysteine restriction significantly decreases obesity in mice via mechanisms that are incompletely defined. Cysteine dioxygenase type 1 (CDO1) mediates the major cysteine catabolism pathway and is highly expressed in hepatocytes and adipocytes. The goal of this study is to determine the impact of this endogenous cysteine catabolism pathway on obesity and fatty liver disease. Methods: Diet-induced obesity and fatty liver disease were studied in hepatocyte-specific CDO1 knockout mice (L-CDO1-KO), hepatocyte-specific CDO1 transgenic mice (L-CDO1-Tg), adipocyte-specific CDO1 knockout mice (Ad-CDO1-KO), and adipocyte-specific CDO1 transgenic mice (Ad-CDO1-Tg). Results: Deletion of hepatocyte CDO1 decreased cysteine conversion to cysteine sulfinic acid, and had modest impact on liver cysteine, GSH, or taurine abundance. When fed a Western diet (WD), L-CDO1-KO mice showed elevated liver injury markers and inflammatory infiltration independent of obesity or steatosis. When fed a fibrogenic high fat/cholesterol/fructose diet (HFCFr), L-CDO1-KO mice developed worsened liver fibrosis. In contrast, L-CDO1-Tg mice fed WD showed lower blood glucose, but similar degree of obesity and steatosis compared to WT mice. Deletion of CDO1 in white and brown adipocytes of Ad-CDO1-KO mice had no effect on WD-induced obesity. In contrast, overexpression of CDO1 in white and brown adipocytes attenuated WD-induced obesity, which resulted in reduced hepatic steatosis. Conclusion: Genetic manipulation of intracellular cysteine catabolism in hepatocytes and adipocytes differentially modulates diet-induced obesity and fatty liver, which warrants future mechanistic investigation to better understand cellular cysteine sensing mechanisms and cysteine control of cell metabolism.