Autophagy-lysosomal pathway is a cellular mechanism ensuring degradation of various macromolecules like proteins or triacylglycerols (TAG). Its disruption is related to many pathological states, including liver steatosis. We compared the effect of short- and long-established steatosis on the intensity of autophagy-lysosomal pathway in rat liver. The experiments were carried out on 3-month old Wistar rats fed standard (SD) or high-fat diet for 2 (HF-2) or 10 (HF-10) weeks. HF diet administered animals accumulated an increased amount of TAG in the liver (HF-2->HF-10). Autophagy flux was up-regulated in HF-2 group but nearly inhibited after 10 weeks of HF administration. The expression of autophagy related genes was up-regulated in HF-2 but normal in HF-10. In contrast, total activities of two lysosomal enzymes, lysosomal lipase (LAL) and acid phosphatase, were unaffected in HF-2 but significantly increased in HF-10 groups. mRNA expression of lysosomal enzymes was not affected by the diet. We conclude that in a state of metabolic unbalance (steatosis), autophagy machinery and lysosomal enzymes expression are regulated independently. The accumulation of TAG in the liver is associated with the increase of total LAL activity and protein expression. In contrast, the autophagy response is bi-phasic and after rapid increase it is significantly diminished. This may represent an adaptive mechanism that counteracts the excessive degradation of substrate, i.e. TAG, and eliminate over-production of potentially hazardous lipid-degradation intermediates.

Institute for Clinical and Experimental Medicine Department of Metabolism and Diabetes Prague Czech Republic

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