Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis

Xiao, Ting; Liang, Xiuci; Liu, Hailan; Zhang, Feng; Meng, Wen; Hu, Fang

doi:10.1530/jme-19-0207

Cited by 25 publications

(14 citation statements)

References 41 publications

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“…Specifically, HSP60 showed to upregulate proliferator-activated receptor gamma coactivator 1 α1 expression, a chief regulator in mitochondrial biogenesis process [51,52]. Furthermore, ER UPR has been suggested to activate mitochondrial UPR [53,54]. These findings are in agreement with our study that showed tunicamycin-associated increases in mitochondrial mass, as well as in the expression of HSP60 and HSPA9 mitochondrial UPR mediators, with HSPA9 being completely inhibited by EUK-134.…”

Section: Discussionsupporting

confidence: 92%

Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells

et al. 2020

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Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation and mitochondrial abnormalities; and is postulated as a potential mechanism involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study investigates the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using the ER stress inducer tunicamycin (24 h) in the presence or absence of a superoxide dismutase/catalase mimetic Eukarion (EUK)-134. Tunicamycin induced maladaptive ER stress, which was mitigated by EUK-134 at the transcriptional level. ER stress promoted mitochondrial dysfunction, described by substantial loss of mitochondrial membrane potential, as well as a reduction in respiratory control ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated by EUK-134. Tunicamycin induced ROS-mediated biogenesis and fusion of mitochondria, which, however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of fission-related markers. Increased cellular ROS generation was observed under ER stress that was prevented by EUK-134, even though no changes in mitochondrial superoxide were noticeable. These findings suggest that targeting ROS generation using EUK-134 can amend aspects of ER stress-induced changes in mitochondrial dynamics and function, and therefore, in instances of chronic ER stress, such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness and dysfunction.

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Section: Discussionsupporting

confidence: 92%

Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells

et al. 2020

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“…De novo lipogenesis occurs in ER and is regulated by membrane proteins sterol regulatory element-binding proteins (SREPB1c and SREPB2, for fatty acids and cholesterol respectively) and related pathways [24,25,38,46]. In presence of insulin resistance, these proteins are upregulated, leading to increased lipogenesis and further lipotoxicity [24,25,28,38,50]. Moreover, the hepatic accumulation of fat can lead to altered composition of ER membrane, leading to impaired functionality [46,51,52].…”

Section: Endoplasmic Reticulum Stress and Mitochondrial Dysfunction In Nafldmentioning

confidence: 99%

Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis

Overi

Carpino

Franchitto

et al. 2020

Cells

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Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. The global prevalence of NAFLD is constantly increasing. NAFLD is a disease spectrum comprising distinct stages with different prognoses. Non-alcoholic steatohepatitis (NASH) is a progressive condition, characterized by liver inflammation and hepatocyte ballooning, with or without fibrosis. The natural history of NAFLD is negatively influenced by NASH onset and by the progression towards advanced fibrosis. Pathogenetic mechanisms and cellular interactions leading to NASH and fibrosis involve hepatocytes, liver macrophages, myofibroblast cell subpopulations, and the resident progenitor cell niche. These cells are implied in the regenerative trajectories following liver injury, and impairment or perturbation of these mechanisms could lead to NASH and fibrosis. Recent evidence underlines the contribution of extra-hepatic organs/tissues (e.g., gut, adipose tissue) in influencing NASH development by interacting with hepatic cells through various molecular pathways. The present review aims to summarize the role of hepatic parenchymal and non-parenchymal cells, their mutual influence, and the possible interactions with extra-hepatic tissues and organs in the pathogenesis of NAFLD.

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“…An important feature of NAFLD and its progression to NASH is mitochondrial stress [ 14 ]. To determine whether the reduction in hepatic steatosis and increase in mitochondrial mass induced by NCT translated to reduced mitochondrial stress, we examined the expression of HSP60, a mitochondrial chaperone that is induced by mitochondrial stress, including HFD [ 15 ] (Fig. 3M ).…”

Section: Resultsmentioning

confidence: 99%

Long-term oral administration of an HNF4α agonist prevents weight gain and hepatic steatosis by promoting increased mitochondrial mass and function

2022

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We report here that the potent HNF4α agonist N-trans-caffeoyltyramine (NCT) promotes weight loss by inducing an increase in mitochondrial mass and function, including fatty acid oxidation. Previously, we found in a short term trial in obese mice that NCT promoted reversal of hepatic steatosis through a mechanism involving the stimulation of lipophagy by dihydroceramides. NCT led to increased dihydroceramide levels by inhibiting dihydroceramide conversion to ceramides. Here, we were able to administer NCT orally, permitting longer term administration. Mice fed NCT mixed with high fat diet exhibited decreased weight. Examination of RNA-seq data revealed an increase in PPARGC1A, a central regulator of mitochondrial biogenesis. In addition to the decreased hepatic steatosis that we found previously, mice fed a high fat diet containing NCT mice weighed substantially less than control mice fed high fat diet alone. They had increased mitochondrial mass, exhibited increased fatty acid oxidation, and had an increased level of NAD. Markers of liver inflammation such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), which are important in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis were decreased by NCT. There was no evidence of any toxicity from NCT consumption. These results indicate that HNF4α is an important regulator of mitochondrial mass and function and support that use of HNF4α to treat disorders of fatty acid excess, potentially including obesity, NAFLD, and NASH.

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Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis

Cited by 25 publications

References 41 publications

Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells

Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells

Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis

Long-term oral administration of an HNF4α agonist prevents weight gain and hepatic steatosis by promoting increased mitochondrial mass and function

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