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Adaption of oxidative phosphorylation machinery compensates for hepatic lipotoxicity in early stages of MAFLD [hepatocyte]

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.

ORGANISM(S): Mus musculus

PROVIDER: GSE198173 | GEO | 2022/06/21

REPOSITORIES: GEO

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Project description:Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.