Molecular mechanisms of nonalcoholic fatty liver disease: Potential role for 12-lipoxygenase

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of pathologies associated with fat accumulation in the liver. NAFLD is the most common cause of liver disease in the United States, affecting up to a third of the general population. It is commonly associated with features of metabolic syndrome, particularly insulin resistance. NAFLD shares the basic pathogenic mechanisms with obesity and insulin resistance, such as mitochondrial, oxidative and endoplasmic reticulum stress. Lipoxygenases catalyze the conversion of poly-unsaturated fatty acids in the plasma membrane—mainly arachidonic acid and linoleic acid—to produce oxidized pro-inflammatory lipid intermediates. 12-Lipoxygenase (12-LOX) has been studied extensively in setting of inflammation and insulin resistance. As insulin resistance is closely associated with development of NAFLD, the role of 12-LOX in pathogenesis of NAFLD has received increasing attention in recent years. In this review we discuss the role of 12-LOX in NAFLD pathogenesis and its potential role in emerging new therapeutics.

Systemic redox imbalance in patients with nonalcoholic fatty liver disease

“…Extensive evidence suggests that oxidative stress play a pivotal role in the disease progression from simple steatosis to steatohepatitis and irreversible damage to the liver . Multiple clinical studies have demonstrated the elevated levels of circulating products of oxidative stress and lipid peroxidation such as malondialdehyde (MDA), oxidized LDL (ox‐LDL), and thiobarbituric acid‐reacting substances (TBARS), as well as depletion of cellular antioxidants, in patients with NAFLD and NASH compared with age‐matched controls . However, the relationship between the extent of steatosis and oxidative stress biomarkers, independent of obesity, has not been previously investigated, as well.…”

“…8 Multiple clinical studies have demonstrated the elevated levels of circulating products of oxidative stress and lipid peroxidation such as malondialdehyde (MDA), oxidized LDL (ox-LDL), and thiobarbituric acid-reacting substances (TBARS), as well as depletion of cellular antioxidants, in patients with NAFLD and NASH compared with age-matched controls. [9][10][11] However, the relationship between the extent of steatosis and oxidative stress biomarkers, independent of obesity, has not been previously investigated, as well. Therefore in the present study, we have determined whether the presence of different liver steatosis grades is related to the oxidative stress and antioxidant status biomarkers in NAFLD patients compared with a group of healthy obese individuals.…”

Comparative Metabolomics Analysis of Cervicitis in Human Patients and a Phenol Mucilage-Induced Rat Model Using Liquid Chromatography Tandem Mass Spectrometry

“…Furthermore, linolenic acid, a polyunsaturated omega-6 fatty acid, is important in the biosynthesis of AA and therefore, some prostaglandins, leukotrienes (LTA 4 , LTB 4 , LTC 4 ), and thromboxane (TXA 2 ). Previous study showed that arachidonic acid and linoleic acid were mianly poly-unsaturated fatty acids in the plasma membrane which could produce oxidized pro-inflammatory lipid intermediates with the conversion by lipoxygenases catalyze (Samala et al, 2017 ). In our study, the level of these poly-unsaturated fatty acids in control group is higher than that in disease group.…”

ALOXE3 is a hepatic fasting-responsive lipoxygenase that enhances insulin sensitivity via hepatic PPARγ

“…This model is also supported by the lack of effect of GW9662 also on ALOXE3-induced thermogenesis. In addition, it should be recognized that genetic disruption of both 12-LOX and 15-LOX in multiple diabetic models largely recapitulates the ALOXE3-mediated enhancement of hepatic insulin sensitivity and reduced hepatic steatosis (15)(16)(17). Therefore, it is quite feasible that -in addition to generating the PPARg ligand 12-KETE -either ALOXE3 activity also depletes 12-LOX products 12-HpETE and 12-HETE ( Fig.…”

“…In humans, a recent large cohort adults with type 2 diabetes demonstrated a potentially protective role for 5-lipoxygenases ALOX5 and ALOX5AP against diabetes mellitus (14). Conversely, ALOX12/15 inhibition in rodent models inhibited oxidative stress, b-cell deterioration, hepatic steatosis and systemic inflammation (15)(16)(17)(18). Together, these data suggest that intracellular lipid intermediary metabolism drives both tissue-level and whole-organism metabolic homeostasis.…”