15. Assesment of clinical and metabolic profile and presentation of lean NAFLD (original) (raw)
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Mitochondrial oxidative function in NAFLD: Friend or foe?
Molecular Metabolism, 2021
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Involvement of free radicals and oxidative stress in NAFLD/NASH
Free Radical Research, 2013
Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease aff ecting high proportion of the population worldwide. NAFLD encompasses a large spectrum of conditions ranging from fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and cancer. NAFLD is considered as a multifactorial disease in relation to the pathogenic mechanisms. Oxidative stress has been implicated in the pathogenesis of NAFLD and NASH and the involvement of reactive oxygen species (ROS) has been suggested. Many studies show the association between the levels of lipid oxidation products and disease state. However, often neither oxidative stress nor ROS has been characterized, despite oxidative stress is mediated by multiple active species by diff erent mechanisms and the same lipid oxidation products are produced by diff erent active species. Further, the eff ects of various antioxidants have been assessed in human and animal studies, but the eff ects of drugs are determined by the type of active species, suggesting the importance of characterizing the active species involved. This review article is focused on the role of free radicals and free radical-mediated lipid peroxidation in the pathogenesis of NAFLD and NASH, taking characteristic features of free radical-mediated oxidation into consideration. The detailed analysis of lipid oxidation products shows the involvement of free radicals in the pathogenesis of NAFLD and NASH. Potential benefi cial eff ects of antioxidants such as vitamin E are discussed.
Intervention by picroside II on FFAs induced lipid accumulation and lipotoxicity in HepG2 cells
Journal of Ayurveda and Integrative Medicine, 2021
Background: Accumulation of free fatty acids (FFAs) in hepatocytes is a hallmark of liver dysfunction and non-alcoholic fatty liver disease (NAFLD). Excessive deposition of FFAs alters lipid metabolism pathways increasing the oxidative stress and mitochondrial dysfunction. Attenuating hepatic lipid accumulation, oxidative stress, and improving mitochondrial function could provide potential targets in preventing progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). Earlier studies with Picrorhiza kurroa extract have shown reduction in hepatic damage and fatty acid infiltration in several experimental models and also clinically in viral hepatitis. Thus, the effect of P. kurroa's phytoactive, picroside II, needed mechanistic investigation in appropriate in vitro liver cell model. Objectives: To study the effect of picroside II on FFAs accumulation, oxidative stress and mitochondrial function with silibinin as a positive control in in vitro NAFLD model. Methodology: HepG2 cells were incubated with FFAs-1000mM in presence and absence of Picroside II-10 mM for 20 hours. Results: HepG2 cells incubated with FFAs-1000mM lead to increased lipid accumulation. Picroside II-10mM attenuated FFAs-induced lipid accumulation (33%), loss of mitochondrial membrane potential (DJm), ATP depletion, and production of reactive oxygen species (ROS). A concomitant increase in cytochrome C at transcription and protein levels was observed. An increase in expression of MnSOD, catalase, and higher levels of tGSH and GSH:GSSG ratios underlie the ROS salvaging activity of picroside II. Conclusion: Picroside II significantly attenuated FFAs-induced-lipotoxicity. The reduction in ROS, increased antioxidant enzymes, and improvement in mitochondrial function underlie the mechanisms of action of picroside II. These findings suggest a need to develop an investigational drug profile of picroside II for NAFLD as a therapeutic strategy. This could be evaluated through the fast-track path of reverse pharmacology.
IJCMC 3 138 LC NRVOLIXIBATINNAFLDTHERAPY LCARNITINDE nr in NAFLD
An Update on Further Progression of NAFLD, NASH with Prospective Therapies Like L-Carnitine (LC), Nicotinamide Ribose (NR) Combination, as well as Apical Sodium Dependent Bile Acids Transporter (ASBT) or Volixibat and Silybin as Alternatives, 2020
L-Carnitine(LC) has a great part in oxidative metabolism as it is needed for moving Long Chain Fatty Acids (LCFA’s) from the cytoplasm into the mitochondrial matrixin which β-oxidation takes place. For getting shifted these LCFA require activation into acyl CoA’s and get converted into acyl carnitines for movement across mitochondrial membrane. These acyl carnitines are under C22 in length can get into mitochondrial matrix [12], where get exchanged with free carnitine, they get converted back to acyl CoA’s and thus can get utilized for β-oxidation [13]. Alsocarnitine is needed for shifting the end products of peroxisomal β-oxidation,medium as well asshort chain acyl CoA’s,out of the peroxisomes for promotingmoremitochondrial processing [14]. Decrease in carnitine amounts correlates with Insulin Resistance (IR) as well as Diet Induced Obesity (DIO) and was pointed to be secondary to prolonged lipid excess, impaired energy metabolism,associated with fat oxidation that is not complete [15].On the other hand, LC administration in obese rats was demonstrated to reinstate carnitine amounts and thereby enhancing metabolic working [15]Nicotinamide Ribose (NR) is a molecule present within diet that is supposed to be the molecule that is responsible for synthesis of nicotinamide adenine nucleotide (NAD+) which increases oxidative metabolism and in mice has been demonstrated to protect HFD induced obesity within mice [16]. Reducing equivalents are supplied by NAD+ for oxidative phosphorylation,that is necessary for oxidative metabolism as well as metabolichomeostasis .In obesity along with other components of Metabolic Syndrome (MetS) like Type 2 Diabetes Mellitus (T2DM) as well as NAFLD [17,18], pointing that with external supplementation to escalate NAD+ levels might help in reducing these conditions.Further NAD+ helps in avoiding extent of injury secondary to Oxidative Stress (OS) [17]. In Obesity as well as NAFLD formation role of Oxidative Stress (OS) has been documented [19]. An escalation of 4-hydroxy nonenal (4-HNE), that represents a marker of Oxidative Stress (OS)-stimulated lipid peroxidation [20] which takes place in NAFLD
Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants
Biomolecules, 2020
Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor ca...
An Update on the Risk Factors Correlating NAFLD with Cardiovascular Disease: Specifically Mitochondrial - Fatty Acids β Oxidation in Liver with Therapeutic Approaches of Avoidance of CVD Associated Mortality-A Systematic Review, 2022
Nonalcoholic fatty liver disease (NAFLD) is a rapidly escalating disorder which impacts a large population worldwide. Nevertheless, cardiovascular disease (CVD) represents the biggest etiology for mortality with regards to patients of NAFLD. Atherogenic dyslipidemia, possessing the properties of plasma hypetriglyceridemia, enhancement of small dense (low density lipoproteins)LDL's particles in addition to reduction of high density lipoproteins cholesterol HDL-C) concentrations are generally seen in patients with a presentation of NAFLD. Thus here we conducted a systematic review utilizing search engine PubMed, Google scholar ;web of science; embase; Cochrane review library utilizing the MeSH terms like NAFLD; CVD; atherosclerosis; insulin resistance(IR); NASH; chronic heart failure; dyslipidemia; hepatokines; endothelial impairment; pro inflammatory cytokines; FA's oxidation; SREBP1c; ChREBP; Sirtuin; LKB1; lipogenesis; mitochondrial lipid β oxidation; genetic mutations from 2010 to 2022. We found a total of 500 articles out of which we selected 143 articles for this review. No meta-analysis was done. Thus here we have detailed the more recent genetic corroboration, with provision of distinctive type of metabolic pathways implicated in NAFLD pathogenesis. Assessment of the genetic results that are accessible pointed that the crucial process that correlated NAFLD modulated dyslipidemia, along with escalation of risk of CVD implied is the changes in the handling of fatty acids β oxidation in the liver mitochondria. NAFLD correlated genes possessing reported anti-atherosclerotic or cardio protective actions in addition to existent Pharmacologic approaches that are concentrated on tackling both treatment of NAFLD in addition to reducing the risk of CVD. Further research demonstrates that inhibitors of de novo'' lipogenesis (DNL) might prove to be of benefit.
Nutrition, 2009
Objective: Mitochondrial dysfunction and hepatocyte cell death have been reported in fatty liver and non-alcoholic steatohepatitis. Our aim in this study was to evaluate whether direct exposure of hepatocytes to extracellular fat could facilitate such deleterious effects. Methods: FaO hepatic cells treated with fat was used as an in vitro model for steatosis. FaO hepatocytes were exposed to 0.1% triacylglycerols using commercially available lipid emulsion (LE) for various periods and studied for production of reactive oxygen species (ROS), mitochondrial function, and cell death parameters. To study the type of cell death, high-mobility group box chromosomal protein 1cellular levels, DNA fragmentation, and caspase activity were evaluated. Results: Cells incubated with LE for 6 h exhibited a marked increase in the production of intracellular ROS. Using treatments with peroxisome proliferator-activated receptor activators, mitochondrial electron-transfer chain inhibitor, and different sources of LE that did or did not contain medium-chain triacylglycerols, the mitochondria were found to be the source of ROS. LE treatment resulted in phosphorylation of adenosine monophosphate-activated protein kinase, accompanied by a decrease in adenosine triphosphate levels. Changes in intracellular ROS and energy levels were followed by cell death. FaO hepatocytes showed a significant reduction in high-mobility group box chromosomal protein-1 and little DNA fragmentation. Incubation with LE for 24 h did not change caspase-3 activity, indicating that hepatocyte death was necrotic. The antioxidant N-acetylcysteine was able to attenuate the changes in intracellular energy levels and ROS levels and to prevent cell death after exposure to LE. Conclusion: These results suggest that exposure of FaO cells to LE leads to an increase in mitochondrial ROS production and a decrease in cellular energy levels followed by necrotic cell death.
Antioxidants
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that can develop into an aggressive form called nonalcoholic steatohepatitis (NASH), which ultimately progresses to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure. Currently, the deterioration of NAFLD is attributed to specific lipid toxicity which could be due to lipotoxicity and/or ferroptosis. In the current study, we evaluated the involvement of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf-2), which is a main activator of phase II metabolism in the two types of lipid-induced toxicity in hepatocytes, lipotoxicity by saturated fatty acids, and in ferroptosis, and the effect of NO donor treatment. AML12 cells were exposed to 600 μM palmitic acid to induce lipotoxicity or treated with 20 μM erastin or 5 μM RSL3 for ferroptosis. In SFA-lipotoxicity, pretreatment with the Nrf2 activator dimethyl fumarate (DMF) managed to ameliorate the cells and the oxidative str...