Dataset Information

MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease.

ABSTRACT:

Background

Non-alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD.

Methods

Wild-type, Md2^-/- and bone marrow reconstitution mice fed with high-fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA-seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies.

Results

Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD-mediated suppression of AMP-activated protein kinase (AMPK). This preservation of AMPK in Md2-deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2-increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression.

Conclusion

Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1-AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non-inflammatory function of MD2 and evidence for the important role of MD2 in NALFD.

SUBMITTER: Luo W

PROVIDER: S-EPMC8958353 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease.

Luo Wu W Ye Lin L Hu Xue-Ting XT Wang Mei-Hong MH Wang Min-Xiu MX Jin Lei-Ming LM Xiao Zhong-Xiang ZX Qian Jian-Chang JC Wang Yi Y Zuo Wei W Huang Li-Jiang LJ Liang Guang G

Clinical and translational medicine 20220301 3

<h4>Background</h4>Non-alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD.<h4>Methods</h4>Wild-type, Md2<sup>-/-</sup> and bone marrow reconstitution mice fed with high-fat diet (HFD) were use ...[more]

PMID: 35343085

Similar Datasets

Project description:BackgroundIn mammals, body mass lost during food restriction is often rapidly regained, and fat is accumulated when ad libitum feeding is resumed. Studies in small cold-acclimated mammals have demonstrated significant mobilization of fat deposits during cold exposure to meet the energy requirements of metabolic thermogenesis. However, no studies to our knowledge have examined the effect of cold exposure on fat accumulation during body mass recovery when refed ad libitum. In this study, striped hamsters restricted to 80% of their regular food intake were then refed ad libitum and exposed to one of three conditions: Intermittent cold temperature (5 °C) for 2 h per day (ICE-2 h/d), intermittent cold temperature (5 °C) for 12 h per day (ICE-12 h/d), or persistent cold exposure (PCE) for four weeks. We measured energy intake, fat deposit mass, serum thyroid hormone levels, and uncoupling protein 1 expression in brown adipose tissue.ResultsThere was no significant effect of intermittent or persistent cold exposure on body mass regain, whereas energy intake increased significantly and total fat deposit decreased in the ICE-12 h/d and PCE groups compared to the ICE-2 h/d group and control group maintained at 23 °C (CON). In the ICE-12 h/d and PCE groups, hamsters had 39.6 and 38.3% higher serum 3,3',5-triiodothyronine levels, respectively, and 81.6 and 71.3% up-regulated expression of uncoupling protein 1, respectively, in brown adipose tissue compared to their counterparts in the CON group. The rate of mitochondrial state III and state IV respiration O2 consumption and the activity of cytochrome c oxidase in BAT and liver were significantly higher in the ICE-12 h/d and PCE groups than in the ICE-2 h/d and CON groups.ConclusionsOur findings suggest thyroid hormone-mediated heat production in brown adipose tissue and liver may be involved in preventing fat accumulation during refeeding in animals frequently or persistently exposed to cold conditions.

Dataset Information

MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease.

Background

Methods

Results

Conclusion

Publications

MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets