Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

Guillory, Bobby; Jawanmardi, Nicole; Iakova, Polina; Anderson, Bárbara; Zhang, Pu; Timchenko, Nikolai A.; García, José Manuel Pérez

doi:10.1111/acel.12688

Cited by 37 publications

(36 citation statements)

References 42 publications

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“…Since aging is an important risk factor for obesity-related diseases (e.g., T2DM, cardiovascular disease, and non-alcoholic fatty liver disease) [17][18][19], we also observed the effects of DOCK5 deficiency on age-and nutrition-related energy metabolism in this study. We found that a deficiency in DOCK5 decreases energy expenditure and leads to increased obesity and IR under conditions of a high-fat diet (HFD) through the Rac1/mTOR/ ribosomal protein S6 (S6) kinase 1 (S6K1)/Akt pathway.…”

Section: Introductionmentioning

confidence: 69%

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

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The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high-fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5-deficient hepatocytes. Importantly, in liver-specific Raptor knockout mice and associated hepatocytes, the effects of an adeno-associated virus (AAV8)-or adenovirus-mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5-Raptor interaction is indispensable for the DOCK5-mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

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Section: Introductionmentioning

confidence: 69%

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

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“…However, our current work challenges this assumption and presents evidence that the development of drugs for inhibition of steatosis might not be sufficient and that therapeutic approaches for NAFLD should include drugs that inhibit liver proliferation. As many other groups, we initially focused our work on the pathways that lead to hepatic steatosis and on a search for small molecules that might inhibit steatosis . In the course of these studies, we found that cyclin D3–cdk4 phosphorylates C/EBPα at Ser193 and increases formation of C/EBPα‐p300 complexes, which in turn activate enzymes of TG synthesis and cause hepatic steatosis .…”

Section: Discussionmentioning

confidence: 99%

“…These proliferative markers include the elevation of gankyrin (Gank), cyclin‐dependent kinase 4 (cdk4), and cyclin D3 and activation of the E2F1 pathway . Several recent reports showed that inhibition of cdk4 prevented and reversed the NAFLD phenotype . Patients with NASH also show elevated cdk4, and the level of elevation correlates with severity of the disease .…”

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confidence: 99%

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) involves development of hepatic steatosis, fibrosis, and steatohepatitis. Because hepatic steatosis appears first in NAFLD animal models, the current therapy development focuses on inhibition of hepatic steatosis, suggesting that further steps of NAFLD will be also inhibited. In this report, we show that the first event of NAFLD is liver proliferation, which drives fibrosis in NAFLD. We have deleted a strong driver of liver proliferation, gankyrin (Gank), and examined development of NAFLD in this animal model under conditions of a high‐fat diet (HFD). We found that proliferating livers of wild‐type mice develop fibrosis; however, livers of Gank liver‐specific knockout (GLKO) mice with reduced proliferation show no fibrosis. Interestingly, an HFD causes the development of strong macrovesicular steatosis in GLKO mice and is surprisingly associated with improvements in animal health. We observed that key regulators of liver biology CCAAT/enhancer binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), p53, and CUG repeat binding protein 1 (CUGBP1) are elevated due to the deletion of Gank and that these proteins support liver functions leading to healthy conditions in GLKO mice under an HFD. To examine the role of one of these proteins in the protection of liver from fibrosis, we used CUGBP1‐S302A knockin mice, which have a reduction of CUGBP1 due to increased degradation of this mutant by Gank. These studies show that reduction of CUGBP1 inhibits steatosis and facilitates liver proliferation, leading to fibrosis and the development of liver tumors. Conclusion: Liver proliferation drives fibrosis, while steatosis might play a protective role. Therapy for NAFLD should include inhibition of proliferation rather than inhibition of steatosis.

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“…In order to determine the existence and levels of OPN in patients with NASH, OPN expression was evaluated in human liver specimens. Expression of lipogenesis-related genes, such as C/EBPa and C/EBPb [19][20][21], was increased in NASH livers. Besides, NASH livers also had markedly higher hepatic gene expression of Cidea [22,23], which is a key player for hepatic lipid storage, and Ly6D [24], presumed to be positively associated with fat content in the liver (Figure 1(A)).…”

Section: Opn Is Elevated In Nash Patientsmentioning

confidence: 98%

Osteopontin acts as a negative regulator of autophagy accelerating lipid accumulation during the development of nonalcoholic fatty liver disease

Tang

Jiang

Jia

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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2020) Osteopontin acts as a negative regulator of autophagy accelerating lipid accumulation during the development of nonalcoholic fatty liver disease, Artificial Cells, Nanomedicine, and Biotechnology, 48:1, 159-168, ABSTRACT Accumulating evidence links osteopontin (OPN), a pro-fibrogenic extracellular matrix protein, to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, liver tissues isolated from nonalcoholic steatohepatitis (NASH) patients expressed higher OPN than those of controls. However, the exact mechanism(s) for this phenomenon is yet to be clarified. Autophagy is the natural, regulated degradation and recycling of a cell's dysfunctional components, in order to maintain homeostasis. Increasing evidence supports that autophagy can constitute an effective Defence mechanism against NAFLD conditions. Herein, we constructed NAFLD mice model by high-fat (HF) and methionine-choline-deficient (MCD) diet and found that OPN is upregulated in livers of NAFLD mice. Besides, secreted OPN inhibited autophagosome-lysosome fusion via binding with its receptors integrin aVb3 and aVb5 in HepG2 cells supplemented with free fatty acids (FFA) and the livers of NAFLD mice. Silencing of OPN attenuated autophagy impairment and reduced lipid accumulation, while supplementation of OPN exhibited the opposite effect. Furthermore, treatment with anti-OPN Ab significantly attenuated steatosis as well as autophagy impairment in the liver. Our findings indicated that OPN plays a vital role in the pathogenesis of the development of NAFLD via autophagy impairment, which might represent a potential new therapeutic target for the treatment of NAFLD. ARTICLE HISTORY

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Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

Cited by 37 publications

References 42 publications

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

Osteopontin acts as a negative regulator of autophagy accelerating lipid accumulation during the development of nonalcoholic fatty liver disease

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