Cytoprotective and suicidal signaling in oxidative stress

Oxidative stress is an imbalance between pro-oxidants and antioxidants in favor of the pro-oxidants, leading to different responses depending on the level of pro-oxidants achieved and the duration of exposure. In this article, we discuss the cytoprotective or suicidal signaling mechanisms associated with oxidative stress by addressing: (I) the development of an acute and mild pro-oxidant state by thyroid hormone administration eliciting the redox upregulation of the expression of proteins affording cell protection as a preconditioning strategy against ischemia-reperfusion liver injury; and (II) the role of prolonged and severe oxidative stress and insulin resistance as determinant factors in the pathogenesis of non-alcoholic fatty liver disease associated with obesity

Combined docosahexaenoic acid and thyroid hormone supplementation as a protocol supporting energy supply to precondition and afford protection against metabolic stress situations

Liver preconditioning (PC) refers to the development of an enhanced tolerance to injuring stimuli. For example, the protection from ischemia–reperfusion (IR) in the liver that is obtained by previous maneuvers triggering beneficial molecular and functional changes. Recently, we have assessed the PC effects of thyroid hormone (T3; single dose of 0.1 mg/kg) and n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs; daily doses of 450 mg/kg for 7 days) that abrogate IR injury to the liver. This feature is also achieved by a combined T3 and the n-3 LCPUFA docosahexaenoic acid (DHA) using a reduced period of supplementation of the FA (daily doses of 300 mg/kg for 3 days) and half of the T3 dosage (0.05 mg/kg). T3-dependent protective mechanisms include (i) the reactive oxygen species (ROS)-dependent activation of transcription factors nuclear factor-κB (NF-κB), AP-1, signal transducer and activator of transcription 3, and nuclear factor erythroid-2-related factor 2 (Nrf2) upregulating the expression of protective proteins. (ii) ROS-induced endoplasmic reticulum stress affording proper protein folding. (iii) The autophagy response to produce FAs for oxidation and ATP supply and amino acids for protein synthesis. (iv) Downregulation of inflammasome nucleotide-bonding oligomerization domain leucine-rich repeat containing family pyrin containing 3 and interleukin-1β expression to prevent inflammation. N-3 LCPUFAs induce antioxidant responses due to Nrf2 upregulation, with inflammation resolution being related to production of oxidation products and NF-κB downregulation. Energy supply to achieve liver PC is met by the combined DHA plus T3 protocol through upregulation of AMPK coupled to peroxisome proliferator-activated receptor-γ coactivator 1α signaling. In conclusion, DHA plus T3 coadministration favors hepatic bioenergetics and lipid homeostasis that is of crucial importance in acute and clinical conditions such as IR, which may be extended to long-term or chronic situations including steatosis in obesity and diabetes. © 2019 IUBMB Life, 71(9):1211–1220, 2019

Hormetic responses of thyroid hormone calorigenesis in the liver: Association with oxidative stress

Thyroid hormone (L-3,3',5-triiodothyronine, T3) exerts calorigenic effects by accelerating mitochondrial O2 consumption through transcriptional activation of respiratory genes, with consequent increased reactive oxygen species (ROS) production. In the liver, ROS generation occurs at different sites of hepatocytes and in the respiratory burst of Kupffer cells, triggering the activation of the transcription factors nuclear factor-jB, signal transducer and activator of transcription 3, and activating protein 1. Under these conditions, the redox upregulation of Kupffer cell-dependent expression of cytokines [tumor necrosis factor-α, interleukin (IL)-1, and IL-6] is achieved, which upon interaction with specific receptors in hepatocytes trigger the expression of antioxidant enzymes (manganese superoxide dismutase, inducible nitric oxide synthase), antiapoptotic proteins (Bcl-2), and acute-phase proteins (haptoglobin, β-fibrinogen). These responses and the promotion of hepatocyte and Kupffe

The importance of the long-chain polyunsaturated fatty acid n-6/n-3 ratio in development of non-alcoholic fatty liver associated with obesity

Non-alcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease that is characterized by hepatocyte triacylglycerol accumulation (steatosis), which can progress to inflammation, fibrosis, and cirrhosis (steatohepatitis). Overnutrition triggers the onset of oxidative stress in the liver due to higher availability and oxidation of fatty acids (FA), with development of hyperinsulinemia and insulin resistance (IR), and n-3 long-chain polyunsaturated FA (n-3 LCPUFA) depletion, with enhancement in the n-6/n-3 LCPUFA ratio favouring a pro-inflammatory state. These changes may lead to hepatic steatosis by different mechanisms, namely, (i) IR-dependent higher peripheral lipolysis and FA flux to the liver, (ii) n-3 LCPUFA depletion-induced changes in DNA binding activity of sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor α (PPAR-α) favouring lipogenesis over FA oxidation, and (iii) hyperinsulinemia-induced act

On the mechanism of thyroid hormone-induced respiratory burst activity in rat polymorphonuclear leukocytes

Administration of single doses of 0.1 mg L-triiodothyronine (T3)/kg for 3 consecutive days to fed rats produced a drastic increase in the respiratory burst activity of isolated polymorphonuclear leukocytes (PMN), stimulated with serum-opsonized zymosan. This effect was evidenced by the 3.8-fold increment in the integrated chemiluminescence, and seems to be primarily related to the enhanced activity of NADPH oxidase elicited by T3 treatment, with the observed higher myeloperoxidase activity playing a contributory role. In these conditions, hyperthyroidism determines a net enhancement in the oxidant capacity of PMN, as the increased rate of O2 - generation found occurs in the absence of changes in the activity of superoxide dismutase. © 1995

Kupffer cell-dependent signaling in thyroid hormone calorigenesis: Possible applications for liver preconditioning

Thyroid hormone (L-3,3′,5-triiodothyronine, T3) is important for the normal function of most tissues, with major actions on O2 consumption and metabolic rate. In the liver, these are due to (i) transcriptional activation of respiratory genes leading to increased reactive O2 species generation in mitochondria and other subcellular sites; and (ii) enhancement in the respiratory burst activity in Kupffer cells (KC), with consequent antioxidant depletion. Under these conditions, the redox upregulation of KC-dependent expression of cytokines (tumor necrosis factor-α, interleukin (IL)-1, IL-6) is achieved, thus triggering the expression of enzymes (inducible nitric oxide synthase, manganese superoxide dismutase), anti-apoptotic proteins (Bcl-2), acute phase proteins (haptoglobin, β-fibrinogen), and hepatocyte proliferation. The above responses (i) represent adaptive mechanisms to re-establish redox homeostasis and promote cell survival; (ii) occur via nuclear factor-κB, signal transducer an

Up-Regulation of PPAR-gamma mRNA Expression in the Liver of Obese Patients: an Additional Reinforcing Lipogenic Mechanism to SREBP-1c Induction

Artículo de publicación ISIIntroduction: Triglyceride accumulation in the liver is an early feature in the development of nonalcoholic fatty liver disease (NAFLD) associated with human obesity, which is a multifactorial syndrome and whose underlying mechanisms are beginning to be understood. Objectives: Liver peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA expression was measured as a signaling mechanism related to steatosis in obese patients with NAFLD. Methods: Liver PPAR-gamma and sterol receptor element-binding protein 1c (SREBP-1c) mRNA(real-time RT-PCR), serum total adiponectin (RIA), and high molecular weight (HMW)-adiponectin (ELISA) levels, and insulin resistance (IR) evolution (homeostasis model assessment-IR) were determined in 22 obese NAFLD patients (16 with steatosis and six with steatohepatitis) who underwent subtotal gastrectomy with gastrojejunal anastomosis in Roux-en-Y and 16 nonobese subjects who underwent laparoscopic cholecystectomy (controls). Results: Liver PPAR-gamma mRNA levels were 112 and 188% higher (P < 0.05) than control values in obese patients with steatosis and steatohepatitis, respectively, who also exhibited 70 and 62% increases in those of SREBP-1c, concomitantly with IR and lower levels of serum total adiponectin and HMW-adiponectin (P < 0.05). Liver PPAR-gamma expression showed positive associations with SREBP-1c mRNA levels (r = 0.86; P < 0.0001), serum insulin levels (r = 0.39; P < 0.01), and homeostasis model assessment-IR (r = 0.60; P < 0.0001), and negative correlations with total adiponectin (r = -0.37; P < 0.01) and HMW-adiponectin (r = -0.51; P < 0.001) levels in serum. Conclusions: PPAR-gamma is up-regulated in the liver of obese patients with NAFLD, representing an additional reinforcing lipogenic mechanism to SREBP-1c induction in the development of hepatic steatosis.Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT), Chile 1060105 109002