NADPH oxidase 1 promotes hepatic steatosis in obese mice and is abrogated by augmented skeletal muscle mass.

Exercise as a lifestyle modification is a frontline therapy for nonalcoholic fatty liver disease (NAFLD), but how components of exercise attenuate steatosis is unclear. To uncouple the effect of increased muscle mass from weight loss in obesity, myostatin knockout mice were bred on a lean and obese db/db background. Myostatin deletion increases gastrocnemius (Gastrocn.) mass and reduces hepatic steatosis and hepatic sterol regulatory element binding protein 1 (Srebp1) expression in obese mice, with no impact on adiposity or body weight. Interestingly, hypermuscularity reduces hepatic NADPH oxidase 1 (Nox1) expression but not NADPH oxidase 4 (Nox4) in db/db mice. To evaluate a deterministic function of Nox1 on steatosis, Nox1 knockout mice were bred on a lean and db/db background. NOX1 deletion significantly attenuates hepatic oxidant stress, steatosis, and Srebp1 programming in obese mice to parallel hypermuscularity, with no improvement in adiposity, glucose control, or hypertriglyceridemia to suggest off-target effects. Directly assessing the role of NOX1 on SREBP1, insulin (Ins)-mediated SREBP1 expression was significantly increased in either NOX1, NADPH oxidase organizer 1 (NOXO1), and NADPH oxidase activator 1 (NOXA1) or NOX5-transfected HepG2 cells versus ?-galactosidase control virus, indicating superoxide is the key mechanistic agent for the actions of NOX1 on SREBP1. Metabolic Nox1 regulators were evaluated using physiological, genetic, and diet-induced animal models that modulated upstream glucose and insulin signaling, identifying hyperinsulinemia as the key metabolic derangement explaining Nox1-induced steatosis in obesity. GEO data revealed that hepatic NOX1 predicts steatosis in obese humans with biopsy-proven NAFLD. Taken together, these data suggest that hypermuscularity attenuates Srebp1 expression in db/db mice through a NOX1-dependent mechanism.NEW & NOTEWORTHY This study documents a novel mechanism by which changes in body composition, notably increased muscle mass, protect against fatty liver disease. This mechanism involves NADPH oxidase 1 (NOX1), an enzyme that increases superoxide and increases insulin signaling, leading to increased fat accumulation in the liver. NOX1 may represent a new early target for preventing fatty liver to stave off later liver diseases such as cirrhosis or liver cancer.

Changing Trends in Liver Biopsy Practices: A Single-Center Analysis.

Introduction To assess the trends for liver biopsy (LB) indications, technique, and histopathologic diagnosis, we retrospectively evaluated liver biopsies in two one-year periods, separated by a decade. Methods A pathology database query was performed for all parenchymal LB in patients over 18 years (11/2017 to 10/2018) and compared to those performed over a one-year period, a decade ago. We identified 427 parenchymal liver biopsies in the recent group and 166 in the decade-old group. Results Elevated liver enzymes are the most common indication for LB. Non-alcoholic fatty liver disease (NAFLD) has become the most common diagnosis compared to 10 years ago, when it was viral hepatitis. Routes of LB were significantly different between the two groups, endoscopic ultrasound-guided liver biopsy (EUS-LB) (80.3% vs 0; p<0.0001), computed tomography-guided (0 vs 42.8%, p<0.0001), percutaneous by gastroenterologists (0% vs 29.5%, p<0.0001), and transjugular-LB (15.1% vs 17.6%, p<0.0001). The adequacy of the tissue for pathological diagnosis was similar, and there was no difference in adverse events. Conclusion At our institution, practice patterns have changed significantly for liver biopsy. There has been an increase in liver biopsy volume, and EUS guidance has become the most common approach for liver biopsy.

Hemorrhagic Ascites Is Associated With Reduced Survival in Cirrhosis: A Systematic Review and Meta-Analysis.

Background: Hemorrhagic ascites is characterized as red blood cell count greater than 10,000/mm3. In cirrhosis, ascites is an event of decompensation, and associated with poor prognosis. However, significance of hemorrhagic ascites is unclear. We conducted a systematic review and meta-analysis to evaluate the significance of hemorrhagic ascites in cirrhotic patients. Methods: We conducted a systematic search in Embase, MEDLINE, Cochrane Central Register of Controlled Trials, the World Health Organization (WHO) International Clinical Trial Registry, and Web of Science Core Collection to identify studies till March 2021, which, in patients with cirrhosis, compared outcomes amongst those with hemorrhagic ascites to those with non-hemorrhagic ascites. The primary outcome was 3-year mortality, and secondary outcomes were acute kidney injury (AKI), hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP) and portal vein thrombosis (PVT). Results: Four studies, with 2,058 cirrhosis patients, were included. Among these, 1,488 patients had non-hemorrhagic ascites and 570 had hemorrhagic ascites. We observed no significant differences in AKI (odds ratio (OR) = 2.55; confidence interval (CI): 0.58 - 11.24), HE (OR = 2.52; CI: 0.70 - 9.05), SBP (OR = 1.66; CI: 0.12 - 22.83) and PVT (OR = 0.99; CI: 0.71 - 1.39). Intensive care unit (ICU) stay was significantly higher in patients with hemorrhagic ascites compared to those with non-hemorrhagic ascites (OR = 1.79; CI: 1.37 - 2.36; I2 = 56%). Pooled 3-year mortality was significantly higher in those with hemorrhagic (72.5% (CI: 68.2-76.4%)) when compared to non-hemorrhagic ascites (57.9% (CI: 55.2-60.6%)) (OR = 2.17; CI: 1.71 - 2.74) with low heterogeneity (I2 = 15%). Conclusions: In patients with cirrhosis, hemorrhagic ascites is a poor prognostic marker, which is associated with increased ICU stay and mortality. Prospective studies are needed to further evaluate significance of hemorrhagic ascites in patients with cirrhosis.

"Bioelectrical impedance analysis in managing sarcopenic obesity in NAFLD".

INTRODUCTION: Sarcopenic obesity and its association with nonalcoholic fatty liver disease (NAFLD) is under-recognized by many healthcare providers in Western medicine due to the lack of awareness and diagnostic guidelines. The result is delayed recognition and treatment, which leads to further health deterioration and increased healthcare costs. Sarcopenic obesity is characterized by the presence of increased fat mass in combination with muscle catabolism related to chronic inflammation and/or inactivity. Previous research has recommended evaluating body composition and physical function performance to adequately diagnose sarcopenic obesity. Body composition analysis can be performed by imaging applications through magnetic resonance imaging, computed tomography, and dual-energy x-ray absorptiometry. Due to the cost of each device and radiation exposure for patients as evidenced in all three modalities, bioelectrical impedance analysis offers a noninvasive approach capable of providing quick and reliable estimates of lean body and fat mass. METHODS AND RESULTS: This review analyzes the current evidence-based literature, indicating a lower skeletal muscle mass and increased visceral adipose tissue correlation to the advancement of fibrosis in fatty liver disease. CONCLUSION: Given the substantial promising research conducted in predominantly Asian populations regarding body tissue distribution and NAFLD, additional prospective research is needed to extend these findings in Western populations.

A Comprehensive Review Evaluating the Impact of Protein Source (Vegetarian vs. Meat Based) in Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a common neurological consequence in patients with cirrhosis and has a healthcare burden of USD 5370 to 50,120 per patient annually. HE significantly hampers the quality of life and is a major cause of morbidity and mortality. Patients with cirrhosis are at a high risk for protein-calorie malnutrition due to altered metabolism. Current evidence has changed the old belief of protein restriction in patients with cirrhosis and now 1.2 to 1.5 g/kg/day protein intake is recommended. Case series and studies with small numbers of participants showed that a vegetarian protein diet decreases the symptoms of HE when compared to a meat-based diet, but the evidence is limited and requires further larger randomized controlled trials. However, vegetable or milk-based protein diets are good substitutes for patients averse to meat intake. Branch chain amino acids (BCAA) (leucine, isoleucine and valine) have also been shown to be effective in alleviating symptoms of HE and are recommended as an alternative therapy in patients with cirrhosis for the treatment of HE. In this review, we provide an overview of current literature evaluating the role of protein intake in the management of HE in cirrhosis.

M3 muscarinic receptor activation reduces hepatocyte lipid accumulation via CaMKKß/AMPK pathway.

Previously, we reported that hepatic muscarinic receptors modulate both acute and chronic liver injury, however, the role of muscarinic receptors in fatty liver disease is unclear. We observed in patients who underwent weight loss surgery, a decrease in hepatic expression of M3 muscarinic receptors (M3R). We also observed that fat loading of hepatocytes, increased M3R expression. Based on these observations, we tested the hypothesis that M3R regulate hepatocyte lipid accumulation. Incubation of AML12 hepatocytes with 1 mM oleic acid resulted in lipid accumulation that was significantly reduced by co-treatment with a muscarinic agonist (pilocarpine or carbachol), an effect blocked by atropine (a muscarinic antagonist). Similar treatment of Hepa 1-6 cells, a mouse hepatoblastoma cell line, showed comparable results. In both, control and fat-loaded AML12 cells, pilocarpine induced time-dependent AMPKα phosphorylation and significantly up-regulated lipolytic genes (ACOX1, CPT1, and PPARα). Compound C, a selective and reversible AMPK inhibitor, significantly blunted pilocarpine-mediated reduction of lipid accumulation and pilocarpine-mediated up-regulation of lipolytic genes. BAPTA-AM, a calcium chelator, and STO-609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, attenuated agonist-induced AMPKα phosphorylation. Finally, M3R siRNA attenuated agonist-induced AMPKα phosphorylation as well as agonist-mediated reduction of hepatocyte steatosis. In conclusion, this proof-of-concept study demonstrates that M3R has protective effects against hepatocyte lipid accumulation by activating AMPK pathway and is a potential therapeutic target for non-alcoholic fatty liver disease.

MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities.

Stress-associated premature senescence (SAPS) is involved in retinal microvascular injury and diabetic retinopathy. We have investigated the role and mode of action of miR-34a in retinal endothelial cells senescence in response to glucidic stress. Human retinal microvascular endothelial cells (HuREC) were exposed to glucidic stress (high glucose (HG) = 25 mM d-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control l-glucose (LG = 25 mM). HG stimulation of HuREC increased the expression of miR-34a and induced cellular senescence. HG also increased the expression of p16ink4a and p21waf1, while decreasing the histone deacetylase SIRT1. These effects were associated with diminished mitochondrial function and loss of mitochondrial biogenesis factors (i.e., PGC-1α, NRF1, and TFAM). Transfection of the cells with miR-34a inhibitor (IB) halted HG-induced mitochondrial dysfunction and up-regulation of senescence-associated markers, whereas miR-34a mimic promoted cellular senescence and mitochondrial dysfunction. Moreover, HG lowered levels of the mitochondrial antioxidants TrxR2 and SOD2, an effect blunted by miR-34a IB, and promoted by miR-34a mimic. 3'-UTR (3'-untranslated region) reporter assay of both genes validated TrxR2 as a direct target of miR-34a, but not SOD2. Our results show that miR-34a is a key player of HG-induced SAPS in retinal endothelial cells via multiple pathways involved in mitochondrial function and biogenesis.

Bi-lobar liver biopsy via EUS enhances the assessment of disease severity in patients with non-alcoholic steatohepatitis.

BACKGROUND: In patients with non-alcoholic fatty liver disease (NAFLD), all-cause mortality increases with fibrosis stage. Liver biopsy (LB), performed predominantly in the right lobe, assesses fibrosis, however, right lobe LB may not be sufficient due to histological variation in different lobes. Endoscopic ultrasound (EUS) allows for biopsy of right and left liver lobes in the same setting. METHODS: This retrospective study assessed for histologic variability amongst left and right liver lobe (L:R) specimens obtained via EUS at a tertiary care center. Between January 2012 and December 2015, 38 NAFLD patients underwent LB, in whom both lobes were sampled. RESULTS: L:R agreement was near-perfect for steatosis (κ = 0.816, 95% CI 0.674, 0.958), good for ballooning (κ = 0.740, 95% CI 0.565, 0.916) and moderate for lobular inflammation (κ = 0.401 95% CI 0.110, 0.692) and fibrosis (κ = 0.473, 95% CI 0.275, 0.672). Intra-observer variability assessed by blinded repeat slide readings was almost perfect for fibrosis and steatosis (κ = 1, 95% CI 1, 1 and κ = 0.939, 95% CI 0.881, 0.997 respectively) and substantial for lobular inflammation (κ = 0.725, 95% CI 0.584, 0.866). Only right lobe assessment underestimated fibrosis in 21%, inflammation in 13%, and steatosis and ballooning in 8% cases. CONCLUSIONS: These data indicate that in NAFLD, due to regional variation, EUS-guided bi-lobar LB improves assessment of disease activity and fibrosis.

Loss of GPR109A/HCAR2 induces aging-associated hepatic steatosis.

GPR109A agonists have been used for the treatment of obesity however, the role of GPR109A in regulating aging-associated alterations in lipid metabolism is unknown. In this study we used Gpr109a-/- mice to investigate the effect of aging in the regulation of lipid accumulation. We observed that in mouse and human livers, in addition to Kupffer cells, GPR109A is expressed in hepatocytes. Over 12 months, compared to wild type (WT), Gpr109a-/- mice gained significantly more weight. Food intake and levels of serum lipids were similar among both groups. Compared to age-matched WT mice, 12-months old Gpr109a-/- mice had significantly increased liver weight, hepatic steatosis and serum markers of liver injury. The fatty liver phenotype in Gpr109a-/- mice was associated with increased hepatic expression of lipogenesis genes and decreased expression of lipolysis genes. Gpr109a-/- mice had significantly increased fat tissues, which was associated with significant increase in adipocyte diameter and surface area. Adipose tissue from Gpr109a-/- mice had increased expression of lipogenesis genes; however, expression of lipolytic genes was similar in both groups. Collectively, these results indicate that during aging, GPR109A modulates de novo lipid accumulation in liver and adipose tissue, and its dysregulation can lead to age-associated obesity and hepatic steatosis.

Carbon monoxide releasing molecule A-1 attenuates acetaminophen-mediated hepatotoxicity and improves survival of mice by induction of Nrf2 and related genes.

Acute liver injury is frequently associated with oxidative stress. Here, we investigated the therapeutic potential of carbon monoxide releasing molecule A-1 (CORM A-1) in oxidative stress-mediated liver injury. Overnight-fasted mice were injected with acetaminophen (APAP; 300 mg/kg; intraperitoneally) and were sacrificed at 4 and 12 h. They showed elevated levels of serum transaminases, depleted hepatic glutathione (GSH) and hepatocyte necrosis. Mice injected with CORM A-1 (20 mg/kg) 1 h after APAP administration, had reduced serum transaminases, preserved hepatic GSH and reduced hepatocyte necrosis. Mice that received a lethal dose of APAP (600 mg/kg), died by 10 h; but those co-treated with CORM A-1 showed a 50% survival. Compared to APAP-treated mice, livers from those co-treated with CORM A-1, had upregulation of Nrf2 and ARE genes (HO-1, GCLM and NQO-1). APAP-treated mice had elevated hepatic mRNA levels of inflammatory genes (Nf-κB, TNF-α, IL1-ß and IL-6), an effect blunted in those co-treated with CORM A-1. In tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells, CORM A-1 augmented cell viability, reduced oxidative stress, activated the nuclear factor erythroid 2-related factor 2 (Nrf2) and anti-oxidant response element (ARE) genes. The molecular docking profile of CO in the kelch domain of Keap1 protein suggested that CO released from CORM A-1 mediated Nrf2 activation. Collectively, these data indicate that CORM A-1 reduces oxidative stress by upregulating Nrf2 and related genes, and restoring hepatic GSH, to reduce hepatocyte necrosis and thus minimize liver injury that contributes to an overall improved survival rate.

Deoxycholylglycine, a conjugated secondary bile acid, reduces vascular tone by attenuating Ca2+ sensitivity via rho kinase pathway.

Patients with cirrhosis have reduced systemic vascular resistance and elevated circulating bile acids (BAs). Previously, we showed that secondary conjugated BAs impair vascular tone by reducing vascular smooth muscle cell (VSMC) Ca2+ influx. In this study, we investigated the effect of deoxycholylglycine (DCG), on Ca2+ sensitivity in reducing vascular tone. First, we evaluated the effects of DCG on U46619- and phorbol-myristate-acetate (PMA)-induced vasoconstriction. DCG reduced U46619-induced vascular tone but failed to reduce PMA-induced vasoconstriction. Then, by utilizing varied combinations of diltiazem (voltage-dependent Ca2+ channel [VDCC] inhibitor), Y27632 (RhoA kinase [ROCK] inhibitor) and chelerythrine (PKC inhibitor) for the effect of DCG on U46619-induced vasoconstriction, we ascertained that DCG inhibits VDCC and ROCK pathway with no effect on PKC. We further assessed the effect of DCG on ROCK pathway. In ß-escin-permeabilized arteries, DCG reduced high-dose Ca2+- and GTPγS (a ROCK activator)-induced vasoconstriction. In rat vascular smooth muscle cells (VSMCs), DCG reduced U46619-induced phosphorylation of myosin light chain subunit (MLC20) and myosin phosphatase target subunit-1 (MYPT1). In permeabilized VSMCs, DCG reduced Ca2+- and GTPγS-mediated MLC20 and MYPT1 phosphorylation, and further, reduced GTPγS-mediated membrane translocation of RhoA. In VSMCs, long-term treatment with DCG had no effect on ROCK2 and RhoA expression. In conclusion, DCG attenuates vascular Ca2+ sensitivity and tone via inhibiting ROCK pathway. These results enhance our understanding of BAs-mediated regulation of vascular tone and provide a platform to develop new treatment strategies to reduce arterial dysfunction in cirrhosis.

Targeting Cholinergic System to Modulate Liver Injury.

Over the past few decades, evidence accumulated to indicate that parasympathetic innervation regulates liver injury and regeneration. Liver derives its parasympathetic input via vagus nerve. In animal models, vagus nerve stimulation and transection are frequently used to determine the impact of parasympathetic input on liver injury responses. Such strategies provide limited understanding of postneuronal mechanisms involved in the regulation of liver injury. The hepatic branch of vagus nerve releases acetylcholine (ACh), which activates muscarinic and nicotinic receptors in hepatocytes as well as non-parenchymal cells to modulate cellular functions. Moreover, vagus nerve releases other neurotransmitters such as vasoactive intestinal peptide (VIP), which also modulates liver injury responses and hemodynamics. Therefore, our understanding of the post-neuronal modulation of liver injury in models utilizing vagus nerve activity remains limited. Gene-silencing technologies and pharmacological manipulation of receptor activity have not only improved our understanding of the role of specific cholinergic receptors but also elucidated the role of various liver cell sub-populations in modulating liver injury response. With advent of organ- and cell-specific transgenic mice, our understanding of neural regulation of liver injury is likely to improve further. This review comprehensively provides current understanding of cholinergic regulation of liver injury, and points to potential therapeutic targets to treat liver injury.

Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management.

With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

Characterization of pressure-mediated vascular tone in resistance arteries from bile duct-ligated rats.

In cirrhosis, changes in pressure-mediated vascular tone, a key determinant of systemic vascular resistance (SVR), are unknown. To address this gap in knowledge, we assessed ex vivo dynamics of pressurized mesenteric resistance arteries (diameter ~ 260 µm) from bile duct-ligated (BDL) and sham-operated (SHAM) rats and determined the underlying mechanisms. At isobaric intraluminal pressure (70 mmHg) as well as with step-wise increase in pressure (10-110 mmHg), arteries from SHAM-rats constricted more than BDL-rats, and had reduced luminal area. In both groups, incubation with LNAME (a NOS inhibitor) had no effect on pressure-mediated tone, and expression of NOS isoforms were similar. TEA, which enhances Ca2+ influx, augmented arterial tone only in SHAM-rats, with minimal effect in those from BDL-rats that was associated with reduced expression of Ca2+ channel TRPC6. In permeabilized arteries, high-dose Ca2+ and γGTP enhanced the vascular tone, which remained lower in BDL-rats that was associated with reduced ROCK2 and pMLC expression. Further, compared to SHAM-rats, in BDL-rats, arteries had reduced collagen expression which was associated with increased expression and activity of MMP-9. BDL-rats also had increased plasma reactive oxygen species (ROS). In vascular smooth muscle cells in vitro, peroxynitrite enhanced MMP-9 activity and reduced ROCK2 expression. These data provide evidence that in cirrhosis, pressure-mediated tone is reduced in resistance arteries, and suggest that circulating ROS play a role in reducing Ca2+ sensitivity and enhancing elasticity to induce arterial adaptations. These findings provide insights into mechanisms underlying attenuated SVR in cirrhosis.

A comparative study on postoperative pain relief in laparoscopic cholecystectomy: Intraperitoneal bupivacaine versus combination of bupivacaine and buprenorphine.

CONTEXT: To assess the analgesic efficacy of the combination of bupivacaine and buprenorphine in alleviating postoperative pain following laparoscopic cholecystectomy. AIMS: Laparoscopic cholecystectomy is comparatively advantageous as it offers less pain in the postoperative period and requires a shorter hospital stay. There are only a few studies performed to evaluate the analgesic efficacy of intraperitoneal instillation of buprenorphine and bupivacaine during laparoscopic cholecystectomy. SETTINGS AND DESIGN: The present research is a randomized, double-blind controlled study conducted in the Department of Anaesthesiology, Dayanand Medical College and Hospital Ludhiana, Punjab after formal ethical approval from Hospital's Ethics Committee. SUBJECTS AND METHODS: This study analyzed 90 adults admitted for elective laparoscopic cholecystectomy. After the procedure, subjects were divided into three equal groups to conduct the study. Three Groups A, B, and C had intraperitoneal instillation of the 25 ml of physiological saline (0.9% normal saline), 0.25% of bupivacaine, 0.25% bupivacaine, and 0.3 mg buprenorphine, respectively. Necessary vitals were monitored and recorded. Visual analog scale (VAS) and verbal rating scale (VRS) scores were recorded and analyzed systematically. STATISTICAL ANALYSIS USED: All observations were analyzed using analysis of variance and Student's t-test. RESULTS: The mean pain scores were highest in Group A compared to Group B and Group C. Mean VAS and VRS scores were highest in Group C comparatively and lowest in Group A. CONCLUSION: Combination of buprenorphine and bupivacaine intraperitoneally is comparatively more effective in relieving postoperative pain in comparison to intraperitoneal instillation of bupivacaine alone for postoperative pain management after laparoscopic cholecystectomy.

Data regarding M1 muscarinic receptor-mediated modulation of hepatic catalase activity in response to oxidative stress.

We recently demonstrated the role of M1 muscarinic receptors (M1R) in modulating oxidative stress in liver and hepatocytes (Urrunaga et al., 2015) [1]. Here we provide data regarding the effect of a novel M1R agonist, VU0357017 (Lebois et al., 2010) [2], on H2O2-mediated hepatocyte injury, the effect of an M1R antagonist VU0255035 (Sheffler et al., 2009) [3] on catalase and super oxide dismutase (SOD) activities in H2O2-treated hepatocytes in vitro, and finally, the effect of M1R ablation on hepatic catalase activity in acetaminophen (APAP)-treated mice.

Naturally Occurring Nrf2 Activators: Potential in Treatment of Liver Injury.

Oxidative stress plays a major role in acute and chronic liver injury. In hepatocytes, oxidative stress frequently triggers antioxidant response by activating nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, which upregulates various cytoprotective genes. Thus, Nrf2 is considered a potential therapeutic target to halt liver injury. Several studies indicate that activation of Nrf2 signaling pathway ameliorates liver injury. The hepatoprotective potential of naturally occurring compounds has been investigated in various models of liver injuries. In this review, we comprehensively appraise various phytochemicals that have been assessed for their potential to halt acute and chronic liver injury by enhancing the activation of Nrf2 and have the potential for use in humans.