Diabetes Metab J.  2021 Sep;45(5):655-674. 10.4093/dmj.2021.0197.

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

• Sousa-Lima I
• Kim HJ
• Jones J
• Kim YB

• KMID: 2520849
• DOI: http://doi.org/10.4093/dmj.2021.0197

Abstract

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.

Keyword

Rho-kinase; AMP-activated protein kinase; Diet, high-fat; Lipogenesis; Nonalcoholic fatty liver disease

Figure

• 

  Fig. 1. Schematic of de novo lipogenesis. Entry points for the main nutrient precursors are shown in gray and the sources of hydrogens of the fatty acyl coenzyme A (acyl-CoA) product are represented by different colors: ‘H+’ hydrogens derived from body water, black ‘H’ for the methyl hydrogens of the initial acetyl-CoA that binds to acyl-CoA synthase, red ‘H’ for the hydrogens derived from nicotinamide adenine dinucleotide phosphate (NADPH) via the pentose phosphate pathway (PPP), and ‘H’ for the hydrogens derived from malonyl-CoA. Also represented is the acyl-CoA synthase complex (ACoAS) following the initial acetylCoA and malonyl-CoA additions. Intracellular acetyl-CoA is represented as distinct mitochondrial (Acetyl-CoAMITO) and cytosolic (acetyl-CoACYTO) pools. CoASH, free acetyl CoA; SCoA, CoA moiety; SCFA, short chain fatty acids; OAA, oxaloacetate; CIT, citrate; AoCS, Co moiety

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  Fig. 2. Role of Rho-associated coiled-coil-containing kinase (ROCK1) in the development of nonalcoholic fatty liver disease (NAFLD). High-fat feeding increases endocannabinoids 2-arachidonoylglycerol and anandamide levels produced from hepatic stellate cells of the liver. Endocannabinoids stimulate ROCK1 activity via cannabinoid receptor type 1 (CB1), which inhibits AMP-activated protein kinase (AMPK) activity. Suppressed AMPK activity then drives the sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenic program, leading to a rise of lipid accumulation. NAFLD ultimately develops with the progression of obesity. On the other hand, it is hypothesized that activated ROCK1 binds to liver X receptor (LXRα) and may prompt the lipogenic pathway through SREBP1c. As an early event of ROCK1 signaling, CB1-mediated Gα12 (or Gαs) activation could be an initial step for ROCK1-dependent de novo lipogenesis. GTP, guanosine triphosphate; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase-1; ACC, acetyl-CoA carboxylase.

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