Abstract：Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for advanced liver disease, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. T2DM is always accompanied by NAFLD as result of a common pathogenesis. Hepatic lipid accumulation and mitochondrial dysfunction proved to be two essential mechanisms for the pathogenesis of T2DM with NAFLD. Regulation of lipophagy and mitophagy in hepatocyte are potential targets for disease therapy. However, autophagy is considered to be a double-edged sword. Moderate autophagy protects liver, yet excessive or failure one aggravates its injury. The evolution of NAFLD could be associated with dynamic regulation of autophagy and additional studies are required. This review aims to investigate the potential value of autophagy regulation in the treatment of NAFLD in type 2 diabetes mellitus, in order to provide innovative targets for therapeutic intervention.
[1] Musso G，Gambino R，Cassader M，et al. Meta analysis：natural history of non-alcoholic fatty liver disease （NAFLD）and diagnostic accuracy of non-invasive tests for liver disease severity [J]. Ann Med，2011，43（8）：617-649.
[2] Anstee QM，Targher G，Day CP. Progression of NAFLD to diabetes mellitus，cardiovascular disease or cirrhosis [J]. Nat Rev Gastroenterol Hepatol，2013，10（6）：330-344.
[3] Vernon G，Baranova A，Younossi ZM. Systematic review：the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults [J]. Aliment Pharmacol Ther，2011，34（3）：274-285.
[4] Nassir F，Ibdah JA. Role of mitochondria in nonalcoholic fatty liver disease [J]. Int J Mol Sci，2014，15（5）：8713-8742.
[5] Lin CW，Zhang H，Li M，et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice [J]. J Hepatol，2013，58（5）：993-999.
[6] Rodriguez ES，Kai Y，Maldonado E， et al. Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes [J]. Autophagy，2009，5（8）：1099-1106.
[7] Mao Y，Yu F，Wang J，et al. Autophagy：a new target for nonalcoholic fatty liver disease therapy [J]. Hepat Med，2016，8：27-37.
[8] Williams KH，Shackel NA，Gorrell MD，et al. Diabetes and nonalcoholic Fatty liver disease：a pathogenic duo [J]. Endocr Rev，2013，34（1）：84-129.
[9] Bechmann LP，Hannivoort RA，Gerken G，et al. The interaction of hepatic lipid and glucose metabolism in liver diseases [J]. J Hepatol，2012，56（4）：952-964.
[10] Klionsky DJ. Autophagy：from phenomenology to molecular understanding in less than a decade [J]. Nat Rev Mol Cell Biol，2007，8（11）：931-937.
[11] Rabinowitz JD，White E. Autophagy and metabolism [J]. Science，2010，330（6009）：1344-1348.
[12] Mehrpour M，Esclatine A，Beau I，et al. Autophagy in health and disease 1. Regulation and significance of autophagy：an overview [J]. Am J Physiol Cell Physiol，2010，298（4）：C776-C785.
[13] Zhang Q，Li Y，Liang T，et al. ER stress and autophagy dysfunction contribute to fatty liver in diabetic mice [J]. Int J Biol Sci，2015，11（5）：559-568.
[14] Eid N，Ito Y，Otsuki Y. Triggering of parkin mitochondrial translocation in mitophagy：implications for liver diseases [J]. Front Pharmacol，2016，7（18）：100.
[15] Singh R，Kaushik S，Wang Y，et al. Autophagy regulates lipid metabolism [J]. Nature，2009，458（7242）：1131-1135. [16] Skop V，Cahová M，Papácková Z，et al. Autophagy-lysosomal pathway is involved in lipid degradation in rat liver [J]. Physiol Res，2012，61（3）：287-297.
[17] Shibata M，Yoshimura K，Furuya N，et al. The MAP1-LC3 conjugation system is involved in lipid droplet formation [J]. Biochem Biophys Res Commun，2009，382（2）：419-423.
[18] Ma D，Molusky MM，Song J，et al. Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD [J]. Mol Endocrinol，2013，27（10）：1643-1654.
[19] Zhang Y，Zeng X，Jin S. Autophagy in adipose tissue biology [J]. Pharmacol Res，2012，66（6）：505-512.
[20] Lemasters JJ. Variants of mitochondrial autophagy：types 1 and 2 mitophagy and micromitophagy（Type 3） [J]. Redox Biol，2014，2：749-754.
[21] Wang Y，Singh R，Xiang Y，et al. Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress [J]. Hepatology，2010，52（1）：266-277.
[22] Rolo AP，Teodoro JS，Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis [J]. Free Radic Biol Med，2012，52（1）：59-69.
[23] Zhou R，Yazdi AS，Menu P，et al. A role for mitochondria in NLRP3 inflammasome activation [J]. Nature，2011，469（7329）：221-225.
[24] Song YM，Lee WK，Lee YH，et al. Metformin restores parkin-mediated mitophagy，suppressed by cytosolic p53 [J]. Int J Mol Sci，2016，17（1）：E122.
[25] Koga H，Kaushik S，Cuervo AM. Altered lipid content inhibits autophagic vesicular fusion [J]. Faseb J，2010，24（8）：3052-3065.
[26] Liu HY，Han J，Cao SY，et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia：inhibition of FoxO1-dependent expression of key autophagy genes by insulin [J]. J Biol Chem，2009，284（45）：31484-31492.
[27] Yang L，Li P，Fu S，et al. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance [J]. Cell Metab， 2010，11（6）：467-478.
[28] Kim KH，Jeong YT，Oh H，et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf 21 as a mitokine [J]. Nat Med，2013，19（1）：83-92.
[29] Petrovski G，Zahuczky G，Májai G，et al. Phagocytosis of cells dying through autophagy evokes a pro-inflammatory response in macrophages [J]. Autophagy，2007，3（5）：509-511.
[30] Sinha RA，Farah BL，Singh BK，et al. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice [J]. Hepatology，2014，59（4）：1366-1380.
[31] Sinha RA，Yen PM. Thyroid hormone-mediated autophagy and mitochondrial turnover in NAFLD [J]. Cell Biosci，2016，6（1）：46.
[32] Liu M，Xu L，Yin L，et al. Potent effects of dioscin against obesity in mice [J]. Sci Rep，2015，5：7973.
[33] Park HW，Lee JH. Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies [J]. Autophagy，2014，10（12）：2385-2386.
[34] Sharma S，Mells JE，Fu PP，et al. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy [J]. PLoS One，2011，6（9）：e25269.
[35] Song YM，Lee YH，Kim JW，et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway [J]. Autophagy，2015，11（1）：46-59.
2017, Vol. 14 
京公网安备 11010502046598号