Loss of mitochondrial amidoxime-reducing component 1 (mARC1) prevents disease progression by reducing fibrosis in multiple mouse models of chronic liver disease.

Background: Metabolic dysfunction-associated steatotic liver disease is a prevalent disease that affects nearly one-third of the global population. Recent genome-wide association studies revealed that a common missense variant in the gene encoding mitochondrial amidoxime reducing component 1 (mARC1) is associated with protection from metabolic dysfunction-associated steatotic liver disease, all-cause cirrhosis, and liver-related mortality suggesting a role for mARC1 in liver pathophysiology; however, little is known about its function in the liver. In this study, we aimed to evaluate the impact of mARC1 hepatoprotective variants on protein function, the effect of loss of mARC1 on cellular lipotoxic stress response, and the effect of global or hepatocyte-specific loss of mARC1 in various mouse models of metabolic dysfunction-associated steatohepatitis and liver fibrosis.

Loss of low-molecular-weight protein tyrosine phosphatase shows limited improvement in glucose tolerance but causes mild cardiac hypertrophy in mice.

Insulin resistance is a major public health burden that often results in other comorbidities including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. An insulin sensitizer has the potential to become a disease-modifying therapy. It remains an unmet medical need to identify therapeutics that target the insulin signaling pathway to treat insulin resistance.

The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice.

Aims/hypothesis: Elucidating the molecular mechanisms of fat accumulation and its metabolic consequences is crucial to understanding and treating obesity, an epidemic disease. We have previously observed that Usp19 deubiquitinating enzyme-null mice (Usp19) have significantly lower fat mass than wild-type (WT) mice. Thus, this study aimed to provide further understanding of the role of ubiquitin-specific peptidase 19 (USP19) in fat development, obesity and diabetes.

Knockout of USP19 Deubiquitinating Enzyme Prevents Muscle Wasting by Modulating Insulin and Glucocorticoid Signaling.

Muscle atrophy arises because of many chronic illnesses, as well as from prolonged glucocorticoid treatment and nutrient deprivation. We previously demonstrated that the USP19 deubiquitinating enzyme plays an important role in chronic glucocorticoid- and denervation-induced muscle wasting. However, the mechanisms by which USP19 exerts its effects remain unknown.

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation.

Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting.

The business of deubiquitination - location, location, location.

A majority of proteins in the cell can be modified by ubiquitination, thereby altering their function or stability. This ubiquitination is controlled by both ubiquitinating and deubiquitinating enzymes (DUBs). The number of ubiquitin ligases exceeds that of DUBs by about eightfold, indicating that DUBs may have much broader substrate specificity.