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Review
. 2023 Jan 3;12(1):120.
doi: 10.3390/antiox12010120.

The Role of Oxidative Inactivation of Phosphatase PTEN and TCPTP in Fatty Liver Disease

Thang Nguyen Huu  1   2 , Jiyoung Park  3 , Ying Zhang  4 , Hien Duong Thanh  2   5 , Iha Park  1 , Jin Myung Choi  1 , Hyun Joong Yoon  1 , Sang Chul Park  6 , Hyun Ae Woo  3 , Seung-Rock Lee  1
Affiliations
Review

The Role of Oxidative Inactivation of Phosphatase PTEN and TCPTP in Fatty Liver Disease

Thang Nguyen Huu et al. Antioxidants (Basel). .

Abstract

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent worldwide. Despite the different etiologies, their spectra and histological feature are similar, from simple steatosis to more advanced stages such as steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Studies including peroxiredoxin knockout models revealed that oxidative stress is crucial in these diseases, which present as consequences of redox imbalance. Protein tyrosine phosphatases (PTPs) are a superfamily of enzymes that are major targets of reactive oxygen species (ROS) because of an oxidation-susceptible nucleophilic cysteine in their active site. Herein, we review the oxidative inactivation of two tumor suppressor PTPs, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and T-cell protein tyrosine phosphatase (TCPTP), and their contribution to the pathogenicity of ALD and NAFLD, respectively. This review might provide a better understanding of the pathogenic mechanisms of these diseases and help develop new therapeutic strategies to treat fatty liver disease.

Keywords: ALD; NAFLD; PTEN; ROS; TCPTP; redox regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Redox regulation of PTEN and TCPTP by ROS. (A). PTEN is reversibly oxidized by ROS and forms a disulfide bond between two cysteine residues. The Trx/TrxR/NADPH system is responsible for the reduction of oxidized PTEN. PTEN may undergo hyperoxidation upon exposure to high levels of ROS. (B). TCPTP oxidation into a reversible -SOH is thought to produce a sulfenamide with an adjacent nitrogen atom. The Trx system also plays a key role in reducing oxidized TCPTP. An amount of TCPTP undergoes hyperoxidation into irreversible -SO2H and -SO3H.
Figure 2
Figure 2
Oxidative inactivation of PTEN in ALD and TCPTP in NAFLD. (A). Ethanol is transported into the cytosol of hepatocytes, where ethanol metabolism occurs. Ethanol oxidation into acetaldehyde is primarily responsible for ADH, and this intermediate acetaldehyde product is converted to acetate by ALDH2 in the mitochondria. This conversion generates ROS via ETC-induced mitochondrial dysfunction. ROS overproduction causes oxidative inactivation of PTEN, leading to Akt hyperactivation and, finally, hepatic steatosis. (B). FFA arising from HFD-induced obesity is transported to the cytosol. Most FFA is metabolized by β-oxidation in the mitochondria. Increased FFA levels are associated with overloaded β-oxidation and subsequent mitochondrial dysfunction. ROS are overproduced due to elevated electron transfer from NADH and FADH2 to the ETC. Enhanced ROS levels induce TCPTP oxidation, activating JAK, STAT-1, and STAT-3 signaling. The hyperactivation of STAT-1 accelerates the development of NASH, while the hyperactivation of STAT-3 triggers HCC.
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