Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases DOI Creative Commons
Bedair Dewidar, Lucia Mastrototaro, Cornelia Englisch

et al.

EBioMedicine, Journal Year: 2023, Volume and Issue: 94, P. 104714 - 104714

Published: July 16, 2023

Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear.Two-day old male C57BL/6j mice received streptozotocin (STZ) placebo (PLC) then high-fat (HFD) regular chow diet (RCD) from week 4 (W4) either W8 W16, yielding control [CTRL = PLC + RCD], diabetes [DIAB STZ obesity [OBES HFD] steatohepatitis [NASH models. Mitochondrial respiration was measured by high-resolution respirometry insulin-sensitive glucose hyperinsulinemic-euglycemic clamps with stable isotope dilution.NASH showed higher steatosis NAFLD activity already at fibrosis W16 (all p < 0.01 vs CTRL). Ballooning increased in DIAB NASH (p At insulin sensitivity 47%, 58% 75% lower DIAB, OBES 0.001 Hepatic uncoupled acid oxidation (FAO)-associated reduced W8, doubled CTRL) correlated biomarkers unfolded protein response (UPR), oxidative stress expression certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic cycle (TCA)-driven 0.0001 CTRL), which positively genes related lipolysis.Hepatic mitochondria adapt various metabolic challenges increasing FAO-driven respiration, is linked dysfunctional UPR, systemic stress, resistance altered lipid metabolism. In a model, TCA-linked reflected mitochondrial adaptation greater turnover.Funding bodies that contributed this study were listed acknowledgements section.

Language: Английский

Role of Insulin Resistance in MAFLD DOI Open Access

Yoshitaka Sakurai,

Naoto Kubota, Toshimasa Yamauchi

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(8), P. 4156 - 4156

Published: April 16, 2021

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as dysfunction-associated (MAFLD). Metabolic this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and syndrome, with insulin resistance common pathophysiology. Imbalance between energy intake expenditure results various tissues alteration gut microbiota, resulting fat accumulation liver. The role genetics also been revealed hepatic fibrosis. In process liver, intracellular damage well further potentiates inflammation, fibrosis, carcinogenesis. Increased lipogenic substrate supply from other tissues, zonation Irs1, factors, including ER stress, play crucial roles increased de novo lipogenesis MAFLD resistance. Herein, we provide an overview factors contributing systemic local progression MAFLD.

Language: Английский

Citations

274
NAFLD: Mechanisms, Treatments, and Biomarkers DOI Creative Commons
Fatiha Nassir

Biomolecules, Journal Year: 2022, Volume and Issue: 12(6), P. 824 - 824

Published: June 13, 2022

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated (MAFLD), is one of the most common causes diseases worldwide. NAFLD growing in parallel with obesity epidemic. No pharmacological treatment available to treat NAFLD, specifically. The reason might be that a multi-factorial an incomplete understanding mechanisms involved, absence accurate and inexpensive imaging tools, lack adequate non-invasive biomarkers. consists accumulation excess lipids liver, causing lipotoxicity progress steatohepatitis (NASH), fibrosis, hepatocellular carcinoma. for pathogenesis current interventions management disease, role sirtuins as potential targets are discussed here. In addition, diagnostic non-coding RNAs emerging biomarkers summarized. availability biomarkers, diagnosis tools crucial detection early signs progression NAFLD. This will expedite clinical trials validation therapeutic treatments.

Language: Английский

Citations

250
Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways DOI Creative Commons
Olufunto O. Badmus,

Sarah A. Hillhouse,

Christopher D. Anderson

et al.

Clinical Science, Journal Year: 2022, Volume and Issue: 136(18), P. 1347 - 1366

Published: Sept. 1, 2022

Abstract The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the combination with metabolic dysfunction form overweight or obesity and insulin resistance. It also associated an increased cardiovascular risk, including hypertension atherosclerosis. Hepatic lipid metabolism regulated by uptake export acids, de novo lipogenesis, utilization β-oxidation. When balance between these pathways altered, hepatic commences, long-term activation inflammatory fibrotic can progress to worsen disease. This review discusses details molecular mechanisms regulating lipids emerging therapies targeting as potential future treatments for MAFLD.

Language: Английский

Citations

174
A subset of Kupffer cells regulates metabolism through the expression of CD36 DOI
Camille Blériot, Emelie Barreby, Garett Dunsmore

et al.

Immunity, Journal Year: 2021, Volume and Issue: 54(9), P. 2101 - 2116.e6

Published: Aug. 31, 2021

Language: Английский

Citations

158
Links between metabolic syndrome and metabolic dysfunction-associated fatty liver disease DOI
Soo Lim, Jin‐Wook Kim, Giovanni Targher

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2021, Volume and Issue: 32(7), P. 500 - 514

Published: May 8, 2021

Language: Английский

Citations

151
Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis DOI Creative Commons
Kuei‐Chuan Lee, Pei-Shan Wu, Han‐Chieh Lin

et al.

Clinical and Molecular Hepatology, Journal Year: 2022, Volume and Issue: 29(1), P. 77 - 98

Published: Oct. 13, 2022

The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. dysfunction lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress would further contribute to hepatocyte injury death, leading inflammation immune in the liver. During healing process, accumulation an excessive amount fibrosis might occur while healing. development NASH liver fibrosis, gut-liver axis, adipose-liver renin-angiotensin system (RAS) may be dysregulated impaired. Translocation bacteria or its end-products entering could activate hepatocytes, Kupffer cells, stellate exacerbating steatosis, inflammation, fibrosis. Bile acids regulate glucose through Farnesoid X receptors intestine. Increased adipose tissue-derived non-esterified fatty aggravate leptin also plays a role fibrogenesis, decreased adiponectin resistance. Moreover, dysregulation peroxisome proliferator-activated liver, adipose, muscle tissues impair metabolism. In addition, RAS acid metabolism, treatment includes lifestyle modification, pharmacological therapy, non-pharmacological therapy. Currently, weight reduction modification surgery most effective However, vitamin E, pioglitazone, obeticholic have been suggested. this review, we will introduce some new clinical trials experimental therapies for related

Language: Английский

Citations

109
Targeting Mitochondrial ROS-Mediated Ferroptosis by Quercetin Alleviates High-Fat Diet-Induced Hepatic Lipotoxicity DOI Creative Commons
Jinjin Jiang, Guofu Zhang,

Jia-Yi Zheng

et al.

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: April 12, 2022

Background: The protective effect of quercetin on nonalcoholic fatty liver disease (NAFLD) has been reported, but its mechanism remains poorly understood. Recently, was reported to be capable inhibiting ferroptosis, which is a recognized type regulated cell death. Moreover, hepatic ferroptosis plays an important role in the progression NAFLD, experimental evidence limited. Hence, our study aimed investigate high-fat diet (HFD)-induced NAFLD and further elucidate underlying molecular mechanism. Methods: C57BL/6J mice were fed either normal (ND), HFD, or HFD supplemented with for 12 weeks. Hepatic lipid peroxidation, steatosis, iron overload examined. In vitro, steatotic L-02 cells used potential Results: We found that caused accumulation liver, rescued by supplementation. Consistent vivo results, alleviated droplet reduced levels reactive oxygen species (ROS) cells. Using mitochondrial ROS (MtROS) scavenger (Mito-TEMPO) specific inhibitor (Fer-1), we remarkably peroxidation reducing MtROS-mediated Conclusion: Our data showed consumption induced triggered ultimately leading lipotoxicity, can quercetin. Findings from this provide new insight into prevention treatment NAFLD.

Language: Английский

Citations

91
Di-2-ethylhexyl phthalate (DEHP) induced lipid metabolism disorder in liver via activating the LXR/SREBP-1c/PPARα/γ and NF-κB signaling pathway DOI Open Access

Yue-Qiang Huang,

Yi-Xi Tang,

Bai-Hao Qiu

et al.

Food and Chemical Toxicology, Journal Year: 2022, Volume and Issue: 165, P. 113119 - 113119

Published: May 7, 2022

Language: Английский

Citations

78
Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation DOI Creative Commons
Pulavendran Sivasami, Cody Elkins, Pamela P. Diaz-Saldana

et al.

Immunity, Journal Year: 2023, Volume and Issue: 56(8), P. 1844 - 1861.e6

Published: July 20, 2023

Language: Английский

Citations

49
The Multifaceted Roles of Macrophages in NAFLD Pathogenesis DOI Creative Commons

Joscha Vonderlin,

Triantafyllos Chavakis, Michael H. Sieweke

et al.

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2023, Volume and Issue: 15(6), P. 1311 - 1324

Published: Jan. 1, 2023

Nonalcoholic fatty liver disease (NAFLD) is the manifestation of metabolic syndrome. NAFLD constitutes a spectrum pathologies ranging from simple hepatic steatosis (nonalcoholic liver) to more progressive form steatohepatitis and fibrosis, which can culminate in cirrhosis hepatocellular carcinoma. Macrophages play multiple roles context pathogenesis by regulating inflammatory responses homeostasis thereby may represent an attractive therapeutic target. Advances high-resolution methods have highlighted extraordinary heterogeneity plasticity macrophage populations activation states thereof. Harmful/disease-promoting as well beneficial/restorative phenotypes co-exist are dynamically regulated, thus this complexity must be taken into consideration strategies concerning targeting. Macrophage includes their distinct ontogeny (embryonic Kupffer cells vs bone marrow-/monocyte-derived macrophages) functional phenotype, for example, phagocytes, lipid- scar-associated macrophages, or restorative macrophages. Here, we discuss multifaceted role macrophages steatosis, steatohepatitis, transition fibrosis carcinoma, focusing on both beneficial maladaptive functions at different stages. We also highlight systemic aspect dysregulation illustrate contribution reciprocal crosstalk between organs compartments (eg, gut-liver axis, adipose tissue, cardiohepatic interactions). Furthermore, current state development pharmacologic treatment options targeting biology.

Language: Английский

Citations

46