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Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.

ABSTRACT: Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury.C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured.In both acute and chronic ethanol condition, macroautophagy was activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo. Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non-alcoholic fatty liver condition.These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury.

SUBMITTER: Lin CW

PROVIDER: S-EPMC3634371 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.

Lin Chih-Wen CW Zhang Hao H Li Min M Xiong Xiwen X Chen Xi X Chen Xiaoyun X Dong Xiaocheng C XC Yin Xiao-Ming XM

Journal of hepatology 20130120 5

<h4>Background & aims</h4>Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulat ...[more]

PMID: 23339953

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Project description:Background: Anoectochilus roxburghii (Orchidaceae) is a traditional Chinese medicinal herb with anti-inflammatory, antilipemic, liver protective, immunomodulatory, and other pharmacological activities. Kinsenoside (KD), which shows protective effects against a variety types of liver damage, is an active ingredient extracted from A. roxburghii. However, the liver protective effects and potential mechanisms of KD in alcoholic liver disease (ALD) remain unclear. This study aimed to investigate the liver protective activity and potential mechanisms of KD in ALD. Methods: AML12 normal mouse hepatocyte cells were used to detect the protective effect of KD against ethanol-induced cell damage. An alcoholic liver injury model was induced by feeding male C57BL/6J mice with an ethanol-containing liquid diet, in combination with intraperitoneal administration of 5% carbon tetrachloride (CCl4) in olive oil. Mice were divided into control, model, silymarin (positive control), and two KD groups, treated with different doses. After treatment, hematoxylin-eosin and Masson's trichrome staining of liver tissues was performed, and serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were determined to assess the protective effect of KD against alcoholic liver injury. Moreover, proteomics techniques were used to explore the potential mechanism of KD action, and ELISA assay, immunohistochemistry, TUNEL assay, and western blotting were used to verify the mechanism. Results: The results showed that KD concentration-dependently reduced ethanol-induced lipid accumulation in AML12 cells. In ALD mice model, the histological examination of liver tissues, combined with the determination of ALT and AST serum levels, demonstrated a protective effect of KD in the alcoholic liver injury mice. In addition, KD treatment markedly enhanced the antioxidant capacity and reduced the endoplasmic reticulum (ER) stress, inflammation, and apoptosis compared with those in the model group. Furthermore, KD increased the phosphorylation level of AMP-activated protein kinase (AMPK), inhibited the mechanistic target of rapamycin, promoted the phosphorylation of ULK1 (Ser555), increased the level of the autophagy marker LC3A/B, and restored ethanol-suppressed autophagic flux, thus activating AMPK-dependent autophagy. Conclusion: This study indicates that KD alleviates alcoholic liver injury by reducing oxidative stress and ER stress, while activating AMPK-dependent autophagy. All results suggested that KD may be a potential therapeutic agent for ALD.

Project description:Background & aimsPhospholipase D1 (PLD1), a phosphatidylcholine-hydrolysing enzyme, is involved in cellular lipid metabolism. However, its involvement in hepatocyte lipid metabolism and consequently non-alcoholic fatty liver disease (NAFLD) has not been explicitly explored.MethodsNAFLD was induced in hepatocyte-specific Pld1 knockout (Pld1(H)-KO) and littermate Pld1 flox/flox (Pld1-Flox) control mice feeding a high-fat diet (HFD) for 20 wk. Changes of the lipid composition in the liver were compared. Alpha mouse liver 12 (AML12) cells and mouse primary hepatocytes were incubated with oleic acid or sodium palmitate in vitro to explore the role of PLD1 in the development of hepatic steatosis. Hepatic PLD1 expression was evaluated in liver biopsy samples in patients with NAFLD.ResultsPLD1 expression levels were increased in the hepatocytes of patients with NAFLD and HFD-fed mice. Compared with Pld1-Flox mice, Pld1(H)-KO mice exhibited decreased plasma glucose and lipid levels as well as lipid accumulation in liver tissues after HFD feeding. Transcriptomic analysis showed that hepatocyte-specific deficiency of PLD1 decreased Cd36 expression in steatosis liver tissues, which was confirmed at the protein and gene levels. In vitro, specific inhibition of PLD1 with VU0155069 or VU0359595 decreased CD36 expression and lipid accumulation in oleic acid- or sodium palmitate-treated AML12 cells or primary hepatocytes. Inhibition of hepatocyte PLD1 significantly altered lipid composition, especially phosphatidic acid and lysophosphatidic acid levels in liver tissues with hepatic steatosis. Furthermore, phosphatidic acid, the downstream product of PLD1, increased the expression levels of CD36 in AML12 cells, which was reversed by a PPARγ antagonist.ConclusionsHepatocyte-specific Pld1 deficiency ameliorates lipid accumulation and NAFLD development by inhibiting the PPARγ/CD36 pathway. PLD1 may be a new target for the treatment of NAFLD.Impact and implicationsThe involvement of PLD1 in hepatocyte lipid metabolism and NAFLD has not been explicitly explored. In this study, we found that the inhibition of hepatocyte PLD1 exerted potent protective effects against HFD-induced NAFLD, which were attributable to a reduction in PPARγ/CD36 pathway-mediated lipid accumulation in hepatocytes. Targeting hepatocyte PLD1 may be a new target for the treatment of NAFLD.

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Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.

Publications

Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.

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