Contrasting Effects of Fasting on Liver-Adipose Axis in Alcohol-Associated and Non-alcoholic Fatty Liver

Rasineni, Karuna; Jordan, Clayton W.; Thomes, Paul; Kubik, Jacy L.; Staab, Elizabeth M.; Sweeney, Sarah; Talmon, Geoffrey A.; Donohue, Terrence M.; McNiven, Mark A.; Kharbanda, Kusum K.; Casey, Carol A.

doi:10.3389/fphys.2021.625352

Cited by 11 publications

(8 citation statements)

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“…Hepatic steatosis could be affected by adipose tissue through FFA release and hepatic uptake of circulating FFAs ( Rasineni et al, 2021 ). Our results showed that the epididymal adipose tissue of HFD-fed mice was enlarged upon AAV- Mir20b treatment; however, the serum FFA levels in these mice were comparable to those in mice treated with the AAV-Control ( Figure 5—figure supplement 4B ).…”

Section: Discussionmentioning

confidence: 99%

Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA

Lee

Jang

Kim

et al. 2021

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA

Lee

Jang

Kim

et al. 2021

eLife

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“…Multiple pathways in adipose-liver crosstalk may contribute to the development and progression of NAFLD/NASH [15, 16]. Based on the present findings, we propose a possible mechanism by which excess adipose tissue-derived inflammatory cytokines, induced by CDAHF feeding, enter the liver and damage hepatocytes to induce liver inflammation and fibrosis.…”

Section: Discussionmentioning

confidence: 53%

“…Increased adipose tissue area is independently associated with NASH or significant fibrosis [14], suggesting that the adipose tissue might be a central target for lifestyle modifications in the patients with NAFLD. Furthermore, a recent study reported that the interaction between the liver and peripheral tissues, mainly adipose tissue, is a key factor in the development of NAFLD [15, 16], indicating a crosstalk between adipose tissue inflammation and NAFLD. This evidence might provide new insights into the putative mechanisms involved in the development of NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Docosahexaenoic Acid Attenuates the Progression of Nonalcoholic Steatohepatitis by Suppressing the Adipocyte Inflammation via the G Protein-Coupled Receptor 120/Free Fatty Acid Receptor 4 Pathway

Nakamoto

Tokuyama²

2022

Pharmacology

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Introduction: Our previous study demonstrated that docosahexaenoic acid (DHA), an endogenous G protein-coupled receptor 120 (GPR120)/free fatty acid receptor (FFAR) 4 agonist, attenuated the liver inflammation in nonalcoholic steatohepatitis (NASH), while exacerbated liver inflammation was observed in the GPR120/FFAR4 knockout (GPR120/FFAR4KO) mice. Recently, abdominal adiposity has been reported to correlate with the severity of inflammation and fibrosis in patients with NASH. In this study, we investigated whether the activation of GPR120/FFAR4 suppressed the inflammation of the adipose tissue and whether these suppressive effects attenuated the development of NASH. Methods: A choline-deficient and 0.1% methionine-containing high-fat (CDAHF) diet was used to create a mouse model of NASH. DHA was orally administered to the mice for 1 week. Epididymal fat pads which collected from the control-fed wild-type (WT) or GPR120/FFAR4KO mice were used as ex vivo white adipose tissue (WAT) culture systems. Results: The mice fed a CDAHF diet for 2 weeks showed NASH-like liver diseases. In the WAT of mice fed with the CDAHF diet, inflammation and fibrosis were significantly increased, and the administration of DHA suppressed these phenomena. In an ex vivo adipocyte culture study, DHA dose-dependently suppressed the lipopolysaccharide-induced inflammation in the adipocyte tissue of WT mice, which was reversed by pretreatment with AH7614, a GPR120/FFAR4 antagonist, but not GPR40 or peroxisome proliferator-activated receptor γ antagonist. Conclusions: These findings suggest that the activation of GPR120/FFAR4 may suppress the inflammation of adipocytes, which could be a key pathway to prevent the development of NASH.

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“…During fasting, the animal mobilizes its body fat reserves to provide non-esterified fatty acids (NEFAs) as an energy source to fulfill its energy requirements. In the liver, NEFAs can be oxidized by mitochondria or re-esterified to form triglycerides (TG) within the endoplasmic reticulum (ER) to be stored in lipid droplets or secreted/exported into the blood as a component of very-low-density lipoprotein (VLDL) [1,2]. Fatty acid oxidation is an important mechanism for maintaining hepatic lipid homeostasis under fasted state.…”

Section: Introductionmentioning

confidence: 99%

Effects of starvation-induced negative energy balance on endoplasmic reticulum stress in the liver of cows

et al. 2022

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Endoplasmic reticulum (ER) stress engages the unfolded protein response (UPR) that serves as an important mechanism for modulating hepatic fatty acid oxidation and lipogenesis.Chronic fasting in mice induced the UPR activation to regulate lipid metabolism. However, there is no direct evidence of whether negative energy balance (NEB) induces ER stress in the liver of cows. This study aimed to elucidate the relationship between the NEB attributed to feed deprivation and ER stress in bovine hepatocytes. Methods:Blood samples and liver biopsy tissues were collected from 6 non-lactating cows before and after their starvation for 48 h. The blood non-esterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA) and glucose level were analyzed. Real-time qPCR and Western blotting were used to explore the regulation of genes associated with UPR and lipid metabolism. Results:The starvation increased the plasma BHBA and NEFA levels and decreased the glucose level.Additionally, the starvation caused significant increases in the mRNA expression level of spliced X-box binding protein 1 (XBP1s) and the protein level of phosphorylated inositol-requiring kinase 1 alpha (p-IRE1α; an upstream protein of XBP1) in the liver. The mRNA expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and its target fatty acid oxidation-and ketogenesis-related genes were significantly upregulated by the starvation-mediated NEB. Furthermore, we found that the mRNA expression levels of lipogenic genes were not significantly changed after starvation. Conclusion:These findings suggest that in the initial stage of NEB in dairy cows, the liver coordinates an adaptive response by activating the IRE1 arm of the UPR to enhance ketogenesis, thereby A c c e p t e d A r t i c l e 4 avoiding a fatty liver status.

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Contrasting Effects of Fasting on Liver-Adipose Axis in Alcohol-Associated and Non-alcoholic Fatty Liver

Cited by 11 publications

References 60 publications

Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA

Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA

Docosahexaenoic Acid Attenuates the Progression of Nonalcoholic Steatohepatitis by Suppressing the Adipocyte Inflammation via the G Protein-Coupled Receptor 120/Free Fatty Acid Receptor 4 Pathway

Effects of starvation-induced negative energy balance on endoplasmic reticulum stress in the liver of cows

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