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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #349422
Title: SIRT3 protects hepatocytes from oxidative injury by enhancing ROS scavenging and mitochondrial integrity

Author
item LIU, JINGXIN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item LI, DAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item TIAN, ZHANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item TONG, QIANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item YE, RICHARD - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item LIN, LIGAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)

Submitted to: Cell Death and Differentiation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/25/2017
Publication Date: 10/26/2017
Citation: Liu, J., Li, D., Tian, Z., Tong, Q., Ye, R.D., Lin, L. 2017. SIRT3 protects hepatocytes from oxidative injury by enhancing ROS scavenging and mitochondrial integrity. Cell Death and Differentiation. 8(10):e3158.

Interpretive Summary: SIRT3 is a protein modifying enzyme, and it is usually activated by diet restriction. SIRT3 is known to be able to suppress free radical levels. The purpose of this study was to determine whether SIRT3 protects liver cells against liver toxins tert-butyl hydroperoxide (t-BHP) and carbon tetrachloride (CCl4). CCl4 is used in refrigerant and as a cleaning agent, while t-BHP is used industrially. We found that increased SIRT3 expression in liver cells protect them against t-BHP or CCl4-induced liver cell death. The underlying mechanism is that SIRT3 modifies several key proteins in liver cells, resulting in increased expression and the activity of enzymes that can detoxify free radicals induced by liver toxins. SIRT3 also increases the factors for DNA damage repair and for the maintenance of normal number and integrity of mitochondria, an important intra-cellular structure. In summary, our study uncovers a protective role of SIRT3 against liver toxins. Our findings suggest that we may treat liver damage caused by CCl4, t-BHP or similar toxins by increasing liver cell SIRT3 levels or by activating SIRT3 enzymatic activity.

Technical Abstract: Evidences of oxidative stress and mitochondrial dysfunction have been recognized in most of clinical and experimental liver diseases. SIRT3, a member of NAD+-dependent deacetylases, is mainly localized in mitochondria. So far, the role of SIRT3 in protecting hepatocytes against oxidative stress remains elusive. Herein, we found SIRT3 protein expression is decreased in tert-butyl hydroperoxide (t-BHP)-treated AML12 cells in vitro and primary hepatocytes from CCl4-injured mice in vivo. To further verify the role of SIRT3 in protecting hepatocytes from t-BHP-induced injury, SIRT3 overexpressed AML12 cell line and primary hepatocytes were generated. SIRT3 overexpressed hepatocytes showed improved cell viability upon t-BHP challenge, with less intracellular reactive oxygen species (ROS) accumulation. SIRT3 overexpression reduced superoxide dismutase 2 acetylation level and stimulated nuclear factor erythroid 2-related factor 2 nuclear translocation to enhance anti-oxidative capacity. Moreover, SIRT3 deacetylated peroxisome proliferator-activated receptor y coactivator 1a to promote mitochondrial biogenesis, and 8-oxoguanine DNA glycosylase 1 to orchestrate DNA repair, resulting in improved mitochondrial function. Through deacetylating Ku70, SIRT3 also abated mitochondrial translocation of dynamin-related protein 1, to attenuate mitochondrial fragmentation in t-BHP-injured hepatocytes. These results suggested that SIRT3 protected hepatocytes against oxidative stress by enhancing ROS scavenging and maintaining mitochondrial integrity.