Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases

Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

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Concepts and Treatment Approaches in Nonalcoholic Fatty Liver Disease

Advances in Hepatology ◽

10.1155/2014/357965 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Dina L. Halegoua-De Marzio ◽

Jonathan M. Fenkel

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

De Novo ◽

Imaging Techniques ◽

De Novo Lipogenesis ◽

Central Adiposity ◽

Preventative Care ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults and is the most common liver disease in Western nations. NAFLD is associated with central adiposity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, and cardiovascular disease. It encompasses the entire spectrum of fatty liver diseases from simple steatosis to nonalcoholic steatohepatitis (NASH) with lobular/portal inflammation, hepatocellular necrosis, and fibrosis. Of those who develop NASH, 15–25% will progress to end stage liver disease and hepatocellular carcinoma over 10–20 years. Its pathogenesis is complex, and involves a state of lipid accumulation due to increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, and increased incidence of de novo lipogenesis. Plasma aminotransferases and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for definitive diagnosis. Many new plasma biomarkers and imaging techniques are now available that should improve the ability to diagnose NAFLD noninvasively Due to its complexity and extrahepatic complications, treatment of NAFLD requires a multidisciplinary approach with excellent preventative care, management, and treatment. This review will evaluate our current understanding of NAFLD, with a focus on existing therapeutic approaches and potential pharmacological developments.

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One-Carbon Metabolism in Fatty Liver Disease and Fibrosis: One-Carbon to Rule Them All

Journal of Nutrition ◽

10.1093/jn/nxaa032 ◽

2020 ◽

Vol 150 (5) ◽

pp. 994-1003

Author(s):

Robin P da Silva ◽

Brandon J Eudy ◽

Rafael Deminice

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Carbon Metabolism ◽

Fatty Liver Disease ◽

De Novo ◽

Future Research ◽

Excessive Alcohol Consumption ◽

Nonalcoholic Fatty Liver ◽

Hepatic Lipid ◽

One Carbon Metabolism

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a term used to characterize a range of disease states that involve the accumulation of fat in the liver but are not associated with excessive alcohol consumption. NAFLD is a prevalent disease that can progress to organ damage like liver cirrhosis and hepatocellular carcinoma. Many animal models have demonstrated that one-carbon metabolism is strongly associated with NAFLD. Phosphatidylcholine is an important phospholipid that affects hepatic lipid homeostasis and de novo synthesis of this phospholipid is associated with NAFLD. However, one-carbon metabolism serves to support all cellular methylation reactions and catabolism of methionine, serine, glycine, choline, betaine, tryptophan, and histidine. Several different pathways within one-carbon metabolism that play important roles in regulating energy metabolism and immune function have received less attention in the study of fatty liver disease and fibrosis. This review examines what we have learned about hepatic lipid metabolism and liver damage from the study of one-carbon metabolism thus far and highlights unexplored opportunities for future research.

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