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Caroline Maag Kristensen:
PGC-1α in the exercise training-mediated regulation of hepatic UPR in mice

Date: 04-01-2018    Supervisor: Henriette Pilegaard

The overall aim of the present PhD project was to examine the effects of acute exercise, lifelong exercise training and exercise training combined with a high-fat high-fructose diet (HFF) on the hepatic unfolded protein response (UPR) and investigate the role of PGC-1α in these responses. To investigate this, the following hypotheses were tested: 1) PGC-1α is required for exercise training-mediated prevention of HFF- induced UPR in the liver. 2) Lifelong exercise training prevents age-induced changes in hepatic UPR and PGC-1α is required for this. 3) An acute bout of exercise and 24h of fasting induces hepatic UPR and autophagy, and elevated muscle PGC-1α dampens these responses. 4) Liver PGC-1α is involved in exerciseinduced hepatic UPR and autophagy.

Study I demonstrated that HFF induced whole-body glucose intolerance as well as increased triglyceride accumulation and reduced IRE1α phosphorylation in the liver. Exercise training prevented HFF-induced glucose intolerance and partially prevented triglyceride accumulation and reduction in IRE1α phosphorylation in the liver. Moreover, the role of PGC-1α in exercise training-induced regulation of hepatic UPR when combined with HFF could not be elucidated, because exercise training only had minor effects in the control mice.

Study II demonstrated that aging mice had elevated hepatic triglyceride content, a tendency for increased BiP protein, decreased PERK protein content as well as increased IRE1α and cleaved ATF6 protein level in the liver. Lifelong exercise training prevented the age-associated increase in IRE1α protein and further decreased PERK protein. PGC-1α was not required for the hepatic UPR in response to exercise training, but seemed to influence the capacity of the liver to induce UPR in a pathway specific manner.

Study III and IV demonstrated that an acute bout of exercise increased liver triglyceride content as well as PERK, eIF2α, IRE1α phosphorylation/protein content and the LC3II/LC3I protein ratio. Cleaved ATF6 protein increased in study IV only. Downstream mRNAs were regulated in the recovery period after exercise. Fasting increased hepatic triglyceride content, cleaved ATF6 protein, HSP72 mRNA, CHOP mRNA and LC3II protein and decreased PERK, eIF2α and IRE1α phosphorylation. Liver PGC-1α was not required for the exercise-induced UPR and autophagy, but muscle PGC-1α seemed to influence the regulation of exercise and fasting-induced UPR in the liver.

In conclusion, HFF reduced the hepatic UPR although hepatic triglyceride content was increased and this was partially prevented with exercise training independent of liver PGC-1α. Aging was associated with increased triglyceride and changes in the capacity and activity of the hepatic UPR, some of which were affected by exercise training independent of PGC-1α. Furthermore, acute exercise induced hepatic UPR and autophagy transiently independent of liver PGC-1α, but muscle PGC-1α seemed to influence parts of the response. Finally, fasting induced pathway-specific regulation of UPR and autophagy, and muscle PGC-1α influenced this regulation. Taken together, hepatic UPR regulation is complex and seems to be pathway specifically regulated by multiple conditions that all challenge the liver metabolically.