FGF21 treatment ameliorates alcoholic fatty liver through activation of AMPK-SIRT1 pathway

Zhu, S. Y.; Ma, Lei; Wu, Yunjie; Ye, Xianlong; Zhang, Tianyuan; Zhang, Qingyang; Rasoul, Lubna Muhi; Liu, Yunye; Guo, Mo; Zhou, Bing; Ren, Guangxin; Li, Deshan

doi:10.1093/abbs/gmu097

Cited by 81 publications

(82 citation statements)

References 31 publications

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“…Asrih et al found that FFA impairs FGF21 action in HepG2 cells [27]. In vivo , FGF21 enhances hepatic insulin sensitivity [19], ameliorates AFLD [30], and regulates the adaptive metabolic response of the liver to prolonged fasting [21]. However, whether and how FGF-21 directly stimulates hepatocytes on glucose uptake is unclear.…”

Section: Discussionmentioning

confidence: 99%

Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis

Liu

Cao

Hou

et al. 2018

Cell Physiol Biochem

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Background/Aims: The liver is a vital organ in vertebrates and has a wide range of functions, including glucose absorption, glycogen storage and glucose production. Fibroblast growth factor (FGF)-21 is a metabolic regulator that is primarily produced by the liver. In this paper, we studied the effect of FGF-21 on glucose metabolism in the liver. Methods: The glucose uptake of cells was detected by 2-Deoxy-d-[³H] glucose; the synergy between insulin and FGF-21 was evaluated. The mRNA expression of GLUT1-4, G6Pase and PEPCK was detected by real-time PCR. Glycogen synthesis was examined by the anthrone method. Blood samples to monitor glucose in db/db diabetic mice were obtained by tail snip. Glucose metabolism in the liver and adipose tissues was observed by fluorescence microscopy. Results: In this study, FGF-21 stimulated glucose uptake by liver cells in both a dose and time-dependent manner, and at the same time, FGF-21 specifically stimulated GLUT1 expression in the liver cells. Furthermore, FGF-21 demonstrated a synergistic effect with insulin on glucose absorption, which is in accordance with enhanced GLUT-1 and -4 expression. Treatment with FGF-21 increased glycogen storage in liver cells. Consistent with in vitro results, FGF-21 lowered the plasma glucose level and stimulated GLUT1 expression and glycogen synthesis in db/db diabetic mice. Simultaneously, FGF-21 inhibited the gene expression of G6Pase and PEPCK. Conclusion: Our results suggest that FGF-21 clears up plasma glucose by stimulating glucose absorption in the liver of diabetic animals and decreases glucose release from the liver by inhibiting gluconeogenesis. Overall, these data indicate that the liver is an important target organ of FGF-21 to regulate glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis

Liu

Cao

Hou

et al. 2018

Cell Physiol Biochem

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“…Among those molecules, AMPK appears to be the most important target of ethanol in liver. AMPK activity is impaired by ethanol exposure and then stimulates downstream effectors, for example, lipin 1 (39), resulting in subsequent inhibition of fatty acid ␤-oxidation and stimulation of lipogenesis that contribute to accumulation of TG in vitro or in vivo (7,40,41). Except for SIRT1 (3), FGF21 (fibroblast growth factor 21) (41), and adiponectin (7), very little is known about the molecular mechanisms leading to the impairment of AMPK activity under ethanol exposure.…”

Section: Discussionmentioning

confidence: 99%

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Li¹,

Xiao²,

et al. 2016

Journal of Biological Chemistry

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Although numerous biological functions of the activating transcription factor 4 (ATF4) have been identified, a direct effect of ATF4 on alcoholic liver steatosis has not been described previously. The aim of our current study is to investigate the role of ATF4 in alcoholic liver steatosis and elucidate the underlying mechanisms. Here, we showed that the expression of ATF4 is induced by ethanol in hepatocytes in vitro and in vivo, and liverspecific ATF4 knock-out mice are resistant to ethanol-induced liver steatosis, associated with stimulated hepatic AMP-activated protein kinase (AMPK) activity. Furthermore, adenovirus-mediated AMPK knockdown significantly reversed the suppressive effects of ATF4 deficiency on ethanol-induced liver steatosis in mice. In addition, ethanol-fed ATF4 knock-out mice exhibit AMPK-dependent inhibition of fatty acid synthase and stimulation of carnitine palmitoyltransferase 1 (CPT1) in the liver. Moreover, hepatic Tribbles homolog 3 (TRB3) expression was stimulated by ethanol in an ATF4-dependent manner, and adenovirus-mediated TRB3 knockdown blocked ATF4-dependent ethanol-induced AMPK inhibition and triglyceride accumulation in AML-12 cells. Finally, TRB3 directly interacted with AMPK to suppress its phosphorylation. Taken together, these results identify the ATF4-TRB3-AMPK axis as a novel pathway responsible for ethanol-induced liver steatosis.People consuming excessive amounts of alcohol for prolonged periods suffer from alcoholic liver disease, which encompasses fatty liver, hepatic inflammation and necrosis, progressive fibrosis, and hepatocellular carcinoma (1). Alcoholic fatty liver is the early stage of alcoholic liver disease, characterized by increased accumulation of fat in the liver, which is usually caused by increased free fatty acid (FFA) 4 uptake, augmented de novo lipogenesis, decreased ␤-oxidation, and/or impaired triglyceride (TG) export (2). Studies have identified some important regulators for ethanol-induced liver steatosis, including sirtuin 1 (SIRT1) (3), sterol regulatory element-binding protein 1 (SREBP-1) (4), peroxisome proliferator-activated receptor ␥ coactivator 1-␣ (PGC-1␣) (5), and 5Ј-adenosine monophosphate-activated protein kinase (AMPK) (6 -8).Among them, AMPK is one of the most important regulators (6 -8). AMPK is a heterotrimeric complex consisting of a catalytic ␣ subunit and two regulatory ␤/␥ subunits. It acts as a key metabolic "switch" by phosphorylating target enzymes involved in lipid metabolism, such as acetyl-CoA carboxylase (ACC) (9). Malonyl-CoA, the product of ACC, is both a precursor for fatty acid biosynthesis and a potent inhibitor of ␤-oxidation at the step regulated by carnitine palmitoyltransferase I (10). AMPK activity is suppressed under ethanol exposure (6) and activation of AMPK by its activator (5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside) or metformin prevents ethanol-induced liver steatosis (11, 12). However, the molecular mechanisms underlying ethanol suppression of AMPK activity remain largely unknown. Activating...

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“…It also increases energy expenditure, FFA oxidation, and mitochondrial function via activating the AMPK-SIRT1-PGC-1/ pathway and UCP1 [70], and counteracts ER stress [65]. On this basis, experimental FGF21 administration improved obesity, diabetes, and NASH [71], and ameliorated diabetic and obesity-related kidney injury in preclinical models of CKD through multiple mechanisms [72,73] (Table S2).…”

Section: The Liver As a Determinant Of Kidney Injurymentioning

confidence: 99%