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Hepatic E4BP4 induction promotes lipid accumulation by suppressing AMPK signaling in response to chemical or diet-induced ER stress.

ABSTRACT: Prolonged ER stress has been known to be one of the major drivers of impaired lipid homeostasis during the pathogenesis of non-alcoholic liver disease (NAFLD). However, the downstream mediators of ER stress pathway in promoting lipid accumulation remain poorly understood. Here, we present data showing the b-ZIP transcription factor E4BP4 in both the hepatocytes and the mouse liver is potently induced by the chemical ER stress inducer tunicamycin or by high-fat, low-methionine, and choline-deficient (HFLMCD) diet. We showed that such an induction is partially dependent on CHOP, a known mediator of ER stress and requires the E-box element of the E4bp4 promoter. Tunicamycin promotes the lipid droplet formation and alters lipid metabolic gene expression in primary mouse hepatocytes from E4bp4^flox/flox but not E4bp4 liver-specific KO (E4bp4-LKO) mice. Compared with E4bp4^flox/flox mice, E4bp4-LKO female mice exhibit reduced liver lipid accumulation and partially improved liver function after 10-week HFLMCD diet feeding. Mechanistically, we observed elevated AMPK activity and the AMPKβ1 abundance in the liver of E4bp4-LKO mice. We have evidence supporting that E4BP4 may suppress the AMPK activity via promoting the AMPKβ1 ubiquitination and degradation. Furthermore, acute depletion of the Ampkβ1 subunit restores lipid droplet formation in E4bp4-LKO primary mouse hepatocytes. Our study highlighted hepatic E4BP4 as a key factor linking ER stress and lipid accumulation in the liver. Targeting E4BP4 in the liver may be a novel therapeutic avenue for treating NAFLD.

SUBMITTER: Yang M

PROVIDER: S-EPMC8011030 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Diet-induced induction of hepatic serine/threonine kinase STK38 triggers proinflammation and hepatic lipid accumulation.

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| S-EPMC10193238 | biostudies-literature

Ramon Flour (Brosimum alicastrum Swartz) Ameliorates Hepatic Lipid Accumulation, Induction of AMPK Phosphorylation, and Expression of the Hepatic Antioxidant System in a High-Fat-Diet-Induced Obesity Mouse Model

Project description: Not available

| S-EPMC10669741 | biostudies-literature

Caveolin1 protects against diet induced hepatic lipid accumulation in mice.

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| S-EPMC5453590 | biostudies-literature

Isoquercetin Improves Hepatic Lipid Accumulation by Activating AMPK Pathway and Suppressing TGF-? Signaling on an HFD-Induced Nonalcoholic Fatty Liver Disease Rat Model.

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| S-EPMC6321444 | biostudies-literature

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| S-EPMC9478455 | biostudies-literature

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| S-EPMC4726366 | biostudies-literature

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Project description:Ultraconserved (uc) RNAs, a class of long non-coding RNAs (lncRNAs), are conserved across humans, mice, and rats, but the physiological significance and pathological role of ucRNAs is largely unknown. Here we show that uc.372 is upregulated in the livers of db/db mice, HFD-fed mice, and NAFLD patients. Gain-of-function and loss-of-function studies indicate that uc.372 drives hepatic lipid accumulation in mice by promoting lipogenesis. We further demonstrate that uc.372 binds to pri-miR-195/pri-miR-4668 and suppresses maturation of miR-195/miR-4668 to regulate expression of genes related to lipid synthesis and uptake, including ACC, FAS, SCD1, and CD36. Finally, we identify that uc.372 is located downstream of the insulinoma-associated 2 (INSM2) gene that is transcriptionally activated by upstream transcription factor 1 (USF1). Our findings reveal a novel mechanism by which uc.372 drives hepatic steatosis through inhibition of miR-195/miR-4668 maturation to relieve miR-195/miR-4668-mediated suppression of functional target gene expression.

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Tschimganidine reduces lipid accumulation through AMPK activation and alleviates high-fat diet-induced metabolic diseases.

Project description:Obesity increases the risk of mortality and morbidity because it results in hypertension, heart disease, and type 2 diabetes. Therefore, there is an urgent need for pharmacotherapeutic drugs to treat obesity. We performed a screening assay using natural products with anti-adipogenic properties in 3T3-L1 cells and determined that tschimganidine, a terpenoid from the Umbelliferae family, inhibited adipogenesis. To evaluate the anti-obesity effects of tschimganidine in vivo. Mice were fed either a normal chow diet (NFD) or a high-fat chow diet (HFD) with or without tschimganidine for 12 weeks. Treatment with tschimganidine decreased lipid accumulation and adipogenesis, accompanied by reduced expression of adipogenesis and lipid accumulation-related factors. Tschimganidine significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased that of AKT. Depletion of AMPK relieved the reduction in lipid accumulation resulting from tschimganidine treatment. Moreover, tschimganidine administration drastically reduced the weight and size of both gonadal white adipose tissue (WAT) and blood glucose levels in high-fat diet-induced obese mice. We suggest that tschimganidine is a potent antiobesity agent, which impedes adipogenesis and improves glucose homeostasis. Tschimganidine can then be evaluated for clinical application as a therapeutic agent. [BMB Reports 2023; 56(4): 246-251].

| S-EPMC10140487 | biostudies-literature

Caffeine reduces hepatic lipid accumulation through regulation of lipogenesis and ER stress in zebrafish larvae.

Project description:Caffeine, the main component of coffee, has showed its protective effect on non-alcoholic fatty liver disease (NAFLD) in many studies. However, the hepatoprotection of caffeine and its mechanisms in zebrafish were unexplored. Thus, this study's intentions are to establish a NAFLD model of zebrafish larvae and to examine the role of caffeine on fatty liver with the model.Growth and the incidence of fatty liver of zebrafish larvae increased with the increased amount of feeding in a dose-dependent manner. The degree of hepatic steatosis of larvae also gradually aggravated with the increased quantity and duration of feeding. Triglyceride contents of zebrafish fed for 20 days significantly increased in model group (180 mg/d) compared with control group (30 mg/d) (P?<?0.001). Significant decreases in body weight and hepatic steatosis rate were observed in 2.5, 5, 8 % caffeine treatment group compared with model group (P?<?0.05). Hepatic lipid accumulation was also significantly reduced in caffeine treatment larvae. Moreover, caffeine treatment was associated with upregulation of lipid ?-oxidation gene ACO and downregulation of lipogenesis-associated genes (SREBP1, ACC1, CD36 and UCP2), ER stress-associated genes (PERK, IRE1, ATF6 and BIP), the inflammatory cytokine genes (IL-1beta and TNF-alpha) and autophagy associated genes (ATG12 and Beclin-1). Protein expression of CHOP, BIP and IL-1beta remarkably reduced in caffeine treatment group compared with model group.We induced hepatoteatosis in zebrafish by overfeeding regimen and demonstrated caffeine have a role in suppression of hepatosteatosis by downregulation of genes associated with lipogenesis, ER stress, inflammatory response and enhancement of lipid oxidation, indicating zebrafish model may be used to identify putative pharmacological targets and to test novel drugs for human NAFLD treatment.

| S-EPMC4647812 | biostudies-literature

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