Molecular mechanisms of the impairment of hepatic autophagy in obesity. Short-term inhibition can be produced through the mTOR complex. Long-term regulation could occur via the transcription factors FoxO and TFEB, which control the transcription of autophagic genes and are inhibited by insulin-induced activation of Akt/PKB and mTOR, respectively. mTOR could be overactivated in the liver, presumably as a result of an increased amino acid concentration following overnutrition and/or hyperinsulinemia. An obesity-induced increase in the calcium-dependent protease calpain-2 could also lead to the degradation of Atg7 and then to defective autophagy. A defect in lysosomal acidification and a reduction in cathepsins B, D, and L expression, which impaired substrate degradation in autolysosomes, have also been reported. Finally, a defect in fusion in organelles including autophagosome-lysosome fusion attributed to HFD-induced changes in the membrane lipid composition. A defect in hepatic autophagy and the associated decrease in the rate of lysosomal degradation contribute to a further increase in the ER stress induced by nutrient overload and insulin resistance.
