scholarly journals Treatment with a polyherbal extract improves fat metabolism, attenuates hepatic stellate cell activation and fibrogenesis.

2021 ◽  
Author(s):  
Pavan Kumar Bellamakondi ◽  
Rizwan Baig Mirza ◽  
Onkar Murthy Mallappa ◽  
Azeemuddin Mohammed ◽  
Hariprasad VR ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Cell Activation ◽  
De Novo ◽  
Stellate Cell ◽  
Stellate Cells ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Polyherbal Formulation

Non-alcoholic steatohepatitis (NASH) involves dysregulations in denovo lipogenesis, fatty acid oxidation, and fibrogenesis. Targeting these pathways holds promise for the treatment of liver disorders. Here we test the extract of a polyherbal formulation (namely Liv.52), which is approved by the Government of India's Drug Regulatory Authority - AYUSH. The current study evaluates the effect of Liv.52 on denovo lipogenesis, fatty acid oxidation, and fibrogenesis. Both in vivo and in vitro model systems were employed to evaluate the efficacy of this polyherbal formulation. Male Wistar rats were dosed with Liv.52 for 2 weeks (250mg/k.g) and expression levels of the genes involved in de novo lipogenesis and fatty acid oxidation pathways were analysed by quantitative real time PCR. Liv.52 treatment resulted in increased hepatic fatty acid oxidation and decreased de novo lipogenesis in these rats. It also reduced hepatic stellate cell activation in CCL4 treated Wistar rats as evidenced by histological evaluation. For in vitro experiments, HepG2 cells were cultured under lipotoxic conditions (using 200 micro molar palmitic acid) and the conditioned media from these cells were used for inducing activation and fibrogenesis in human hepatic stellate cells (HHSteC). Treatment with lipotoxic conditioned media resulted in activation of hepatic stellate cells and fibrogenesis, as evidenced by increased expression of alpha-smooth muscle actin (alpha-SMA), and desmin (markers of stellate cell activation) and increased levels of collagen and lumican (markers of fibrogenesis). Treatment with Liv.52 reversed the up-regulation of alpha-SMA, collagen and lumican levels in HHSteC cells. These results indicate that Liv.52 exerts its hepatoprotective effect by improving fatty acid metabolism and fibrogenesis.

scholarly journals Sex Differences in Hepatic De Novo Lipogenesis with Acute Fructose Feeding

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1263 ◽  
Author(s):  
Wee Low ◽  
Thomas Cornfield ◽  
Catriona Charlton ◽  
Jeremy Tomlinson ◽  
Leanne Hodson
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
De Novo ◽  
Dietary Fatty Acid ◽  
De Novo Lipogenesis ◽  
Liver Fat ◽  
Acid Oxidation ◽  
Free Sugars ◽  
Isotope Tracer ◽  
High Fructose

Dietary free sugars have received much attention over the past few years. Much of the focus has been on the effect of fructose on hepatic de novo lipogenesis (DNL). Therefore the aim of the present study was to investigate the effects of meals high and low in fructose on postprandial hepatic DNL and fatty acid partitioning and dietary fatty acid oxidation. Sixteen healthy adults (eight men, eight women) participated in this randomised cross-over study; study days were separated by a 4-week wash-out period. Hepatic DNL and dietary fatty acid oxidation were assessed using stable-isotope tracer methodology. Consumption of the high fructose meal significantly increased postprandial hepatic DNL to a greater extent than consumption of the low fructose meal and this effect was evident in women but not men. Despite an increase in hepatic DNL, there was no change in dietary fatty acid oxidation. Taken together, our data show that women are more responsive to ingestion of higher amounts of fructose than men and if continued over time this may lead to changes in hepatic fatty acid partitioning and eventually liver fat content.

scholarly journals Progesterone receptor membrane component 1 reduces cardiac steatosis and lipotoxicity via activation of fatty acid oxidation and mitochondrial respiration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sang R. Lee ◽  
Jun H. Heo ◽  
Seong Lae Jo ◽  
Globinna Kim ◽  
Su Jung Kim ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Progesterone Receptor ◽  
Fatty Acid Oxidation ◽  
Mitochondrial Respiration ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Membrane Component ◽  
Markers Of Inflammation ◽  
Receptor Membrane

AbstractObesity is implicated in cardiovascular disease and heart failure. When fatty acids are transported to and not adequately oxidized in cardiac cells, they accumulate, causing lipotoxicity in the heart. Since hepatic progesterone receptor membrane component 1 (Pgrmc1) suppressed de novo lipogenesis in a previous study, it was questioned whether cardiac Pgrmc1 protects against lipotoxicity. Hence, we focused on the role of cardiac Pgrmc1 in basal (Resting), glucose-dominant (Refed) and lipid-dominant high-fat diet (HFD) conditions. Pgrmc1 KO mice showed high FFA levels and low glucose levels compared to wild-type (WT) mice. Pgrmc1 KO mice presented low number of mitochondrial DNA copies in heart, and it was concomitantly observed with low expression of TCA cycle genes and oxidative phosphorylation genes. Pgrmc1 absence in heart presented low fatty acid oxidation activity in all conditions, but the production of acetyl-CoA and ATP was in pronounced suppression only in HFD condition. Furthermore, HFD Pgrmc1 KO mice resulted in high cardiac fatty acyl-CoA levels and TG level. Accordingly, HFD Pgrmc1 KO mice were prone to cardiac lipotoxicity, featuring high levels in markers of inflammation, endoplasmic reticulum stress, oxidative stress, fibrosis, and heart failure. In vitro study, it was also confirmed that Pgrmc1 enhances rates of mitochondrial respiration and fatty acid oxidation. This study is clinically important because mitochondrial defects in Pgrmc1 KO mice hearts represent the late phase of cardiac failure.

scholarly journals Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

Diabetes ◽  
2006 ◽  
Vol 55 (10) ◽  
pp. 2688-2697 ◽  
Author(s):  
A. L. Carey ◽  
G. R. Steinberg ◽  
S. L. Macaulay ◽  
W. G. Thomas ◽  
A. G. Holmes ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Interleukin 6 ◽  
Glucose Disposal ◽  
Acid Oxidation ◽  
Amp Activated Protein Kinase

scholarly journals Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

2021 ◽  
Author(s):  
Caterina Bartolacci ◽  
Cristina Andreani ◽  
Goncalo Dias do Vale ◽  
Stefano Berto ◽  
Margherita Melegari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Fatty Acid ◽  
Metabolic Networks ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Genetically Engineered ◽  
De Novo Lipogenesis ◽  
Main Process

Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

scholarly journals Critical Role for Hepatocyte-Specific eNOS in NAFLD and NASH

2021 ◽  
Author(s):  
Rory P. Cunningham ◽  
Mary P. Moore ◽  
Ryan J. Daskek ◽  
Grace M. Meers ◽  
Takamune Takahashi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Critical Role ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Nonalcoholic Fatty Liver ◽  
Mitochondrial Fatty Acid ◽  
Endothelial Nitric Oxide

Regulation of endothelial nitric oxide synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty liver disease (NAFLD) development and progression to steatohepatitis (NASH). In this study, we show genetic deletion and viral knockdown of hepatocyte-specific eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, increased mitochondrial H<sub>2</sub>O<sub>2</sub> emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response. Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased hepatocyte mitochondrial respiration and attenuated western diet induced NASH. Moreover, patients with elevated NAFLD activity score (histology score of worsening steatosis, hepatocyte ballooning, and inflammation) exhibited reduced hepatic eNOS expression which correlated with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein expression of mitophagy protein BNIP3. The current study reveals an important molecular role for hepatocyte-specific eNOS as a key regulator of NAFLD/NASH susceptibility and mitochondrial quality control with direct clinical correlation to patients with NASH.

scholarly journals Pomegranate vinegar feeding enhances fatty acid oxidation: In vitro and in vivo

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
YEOJIN PARK ◽  
Elly Ok ◽  
Hyo Jung Lee ◽  
Ji Yeon Kim ◽  
Mi Kyung Kim ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ling Tao ◽  
Yi Liu ◽  
Chao Xin ◽  
Weidong Huang ◽  
Lijian Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Glucose Utilization ◽  
C2c12 Cells ◽  
Time Dependent ◽  
Acid Oxidation ◽  
Ampk Signaling

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P<0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P<0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P<0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P<0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P<0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.

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