Dataset Information

Adaption of oxidative phosphorylation machinery compensates hepatic lipotoxicity in early stages of MAFLD; PMID:35743314

ABSTRACT: Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.https://pubmed.ncbi.nlm.nih.gov/35743314/

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Non-alcoholic Fatty Liver Disease,Fatty Liver Disease

SUBMITTER: Birgit Knebel

LAB HEAD: Birgit Knebel

PROVIDER: PXD032214 | Pride | 2022-08-02

REPOSITORIES: Pride

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			Action	DRS
	checksum.txt	Txt
	mHepatoLys_C57_7234_2h_DIA34.raw	Raw
	mHepatoLys_C57_7235_2h_DIA34.raw	Raw
	mHepatoLys_C57_7236_2h_DIA34.raw	Raw
	mHepatoLys_C57_7237_2h_DIA34.raw	Raw

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Publications

Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD.

Fahlbusch Pia P Nikolic Aleksandra A Hartwig Sonja S Jacob Sylvia S Kettel Ulrike U Köllmer Cornelia C Al-Hasani Hadi H Lehr Stefan S Müller-Wieland Dirk D Knebel Birgit B Kotzka Jörg J

International journal of molecular sciences 20220620 12

Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased h ...[more]

PMID: 35743314

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Project description:Background and aim: The Insulin-like growth factor (IGF) axis is increasingly suggested to be involved in fatty liver disease and progression. We identified IGFBP2 as transcriptional regulatory effect network in liver steatosis and conducted a translational approach of its role in liver pathology from mouse to human, and whether it is influenced by conventional clinical intervention that mitigate hepatic steatosis. Methods: Primary hepatocytes from either C57Bl6 controls, alb-SREBP-1c mice with moderate transgene induced hepatic lipid accumulation or aP2-SREBP-1c mice with massive ectopic hepatic lipid accumulation, were analyzed to identify regulatory networks based on differentially regulated hepatic gene expression. In a translational approach, serum of morbidly obese patients with and without diabetes and biopsy-proven NAFLD were used for ELISA-based validation of mouse data. Moreover, sera of patients undergoing intervention were analyzed and correlated to liver fat content. Results: Comparative knowledge-based transcriptome analysis identified IGFBP2 as top score regulatory effect network between moderate and aggravated fatty liver in mouse models. The reduced expression of IGFBP2 in aP2-SREPB-1c progressed fatty liver associated with Igfbp2 promoter hypermethylation. Reduced secretion of IGFBP2 from aP2-SREBP-1c hepatocytes was reflected in the circulation of the animals. In this phenotype, reductions of IGFBP2 were accompanied by reduced fatty acid oxidation and increased methyltransferase and SIRT activity. Physiologically, IGFBP2 has no direct impact on lipid metabolism but might modulate IGF1 action on de novo lipogenesis. In humans, IGFBP2 levels declined from non-obese men to morbidly obese men with NAFLD and NASH. In intervention study reductions in liver fat correlated with restoration of IGFBP2 serum levels to values found in healthy individuals in morbidly obese patients following bariatric surgery. Conclusion: In hepatic metabolism changes of IGFBP2 abundance is connected to lipid metabolism whereas changes in IGFBP2 secretion were directly reflected in the circulation. IGFBP2 serum concentration correlates with the degree of fatty liver, which seems to be related to plasticity of the adipose tissue. These data provide IGFBP2 as a potential non-invasive biomarker for fatty liver disease directly reflecting the degree of impaired liver function with the potential to indicate progressed fatty liver disease.