scholarly journals Hepatic miR-20b promotes nonalcoholic fatty liver disease by suppressing PPARα

2021 ◽  
Author(s):  
Yo Han Lee ◽  
Hyun-Jun Jang ◽  
Sounkou Kim ◽  
Sun Sil Choi ◽  
Keon Woo Khim ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Network Analysis ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Metabolic Reprogramming ◽  
Deficient Diet ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic metabolic reprogramming that leads to excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic metabolic reprogramming, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods: Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in NAFLD patients, we revealed that miR-20b specifically targets PPARα. miR-20b mimic and anti-miR-20b were administered to hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of miR-20b in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by miR-20b. Results: We revealed that miR-20b specifically targets PPARα through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of miR-20b was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of miR-20b significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, miR-20b significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARα. In miR-20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of miR-20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Conclusions: Taken together, our results demonstrate that the novel miR-20b targets PPARα, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding: This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340), the Future-leading Project Research Fund (1.210034.01) of UNIST and the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1I1A1A01074940).

scholarly journals Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yo Han Lee ◽  
Hyun-Jun Jang ◽  
Sounkou Kim ◽  
Sun Sil Choi ◽  
Keon Woo Khim ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Network Analysis ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Synergic Effect ◽  
Hepatic Lipid Metabolism ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid

Background:Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods:Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model. Results:We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. Conclusions:Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding:This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940), and the Future-leading Project Research Fund (1.210034.01) of UNIST.

scholarly journals How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

2021 ◽  
Vol 15 (1) ◽  
pp. 21-35
Author(s):  
Yana Geng ◽  
Klaas Nico Faber ◽  
Vincent E. de Meijer ◽  
Hans Blokzijl ◽  
Han Moshage
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Lipid Uptake ◽  
Cellular Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Lipid Species ◽  
Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). Purposeand Aim This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease

2016 ◽  
Vol 35 (1) ◽  
pp. 175-182 ◽  
Author(s):  
Prasanthi Jegatheesan ◽  
Stéphanie Beutheu ◽  
Gabrielle Ventura ◽  
Gilles Sarfati ◽  
Esther Nubret ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Hepatic Lipid Metabolism ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Alcoholic Fatty Liver Disease

scholarly journals Playing Jekyll and Hyde—The Dual Role of Lipids in Fatty Liver Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2244
Author(s):  
Martijn R. Molenaar ◽  
Louis C. Penning ◽  
J. Bernd Helms
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Fibrosis ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid Accumulation

Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in hepatocytes can progress into hepatic fibrosis, a condition induced by the activation of stellate cells. In their resting state, these cells store substantial quantities of fat-soluble vitamin A (retinyl esters) in large lipid droplets. During activation, these lipid organelles are gradually degraded. Hence, treatment of fatty liver disease is treading a tightrope—unsophisticated targeting of hepatic lipid accumulation might trigger problematic side effects on stellate cells. Therefore, it is of great importance to gain more insight into the highly dynamic lipid metabolism of hepatocytes and stellate cells in both quiescent and activated states. In this review, part of the special issue entitled “Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis 2020”, we discuss current and highly versatile aspects of neutral lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

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