PGC-1αin hepatic UPR during high-fat high-fructose diet and exercise training in mice

Abstract

Diet‐induced obesity is associated with hepatic steatosis, which has been linked with activation of the unfolded protein response (UPR). PGC‐1α is a transcriptional coactivator involved in exercise training‐induced adaptations in muscle and liver. Therefore, the aim of this study was to test the hypothesis that PGC‐1α is required for exercise training‐mediated prevention of diet‐induced steatosis and UPR activation in liver. Male liver‐specific PGC‐1α knockout (LKO) and littermate floxed (lox/lox) mice were divided into two groups receiving either control diet (CON) or high‐fat high‐fructose diet (HFF). After 9 weeks, half of the HFF mice were treadmill exercise trained for 4 weeks (HFF+ExT), while the rest were kept sedentary. HFF resulted in increased body and liver weight, adiposity, hepatic steatosis and whole body glucose intolerance as well as decreased hepatic IRE1α phosphorylation. Exercise training prevented the HFF‐induced weight gain and partially prevented increased liver weight, adiposity and glucose intolerance, but with no effect on liver triglycerides. In addition, BiP protein and CHOP mRNA content increased with exercise training compared with CON and HFF, respectively. Lack of PGC‐1α in the liver only resulted in minor changes in the PERK pathway. In conclusion, this study provides evidence for dissociation between diet‐induced hepatic triglyceride accumulation and hepatic UPR activation. In addition, PGC‐1α was not required for maintenance of basal UPR in the liver and due to only minor exercise training effects on UPR further studies are needed to conclude on the potential role of PGC‐1α in exercise training‐induced adaptations in hepatic UPR.

Loss of TRIM67 Attenuates the Progress of Obesity-Induced Non-Alcoholic Fatty Liver Disease

“…In obese conditions, different results are present of hepatic PGC-1α expression. Multiple studies reported that high-fat diets induced hepatic PGC-1α expression [46][47][48][49], while others showed decreased expression of that in an obese liver [50,51]. These results display the complex roles of PGC-1α in regulating liver function.…”

GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans

“…However, others have demonstrated metformin to increase hepatic GDF15 mRNA and secretion via activating transcription factor 4 (AFT4) and CCAAT-enhancer-binding protein homologous protein (CHOP) involved in cell stress ( 13 , 31 ), a signaling pathway also found in a mouse model of non-alcoholic steatohepatitis to increase the GDF15 mRNA level in the liver ( 36 ). Hepatic ER stress increases in mice after exercise ( 37 , 38 ), but a recent study in mice demonstrated that during exercise, also in mice, GDF15 secretion occurs independent of ER stress/CHOP ( 39 ). In humans, in vivo , regulation of plasma GDF15 by the glucagon to insulin ratio is compatible to other physiological and pathophysiological conditions.…”

Aerobic Exercise‐Assisted Cardiac Regeneration by Inhibiting Tryptase Release in Mast Cells after Myocardial Infarction

“…Heart failure with an ejection fraction < 55% is clear. Calculation of cardiac output was estimated as (end − diastolic volume–end − systolic volume) × heart rate (ml/min) [ 3 ] ( Table 1 ).…”

“…The signaling paths that are triggered subsequent cardiomyocyte death start acute amendatory alterations in the heart that could be fragmented into first and delayed steps. The first step includes the substitution of necrotic cells with fibrotic scar establishment, lengthening of cardiomyocytes, and diminishing of the infarct area [ 3 , 4 ]. The delayed step will move forward indeterminately and finally happens in heart failure [ 3 ].…”

“…The first step includes the substitution of necrotic cells with fibrotic scar establishment, lengthening of cardiomyocytes, and diminishing of the infarct area [ 3 , 4 ]. The delayed step will move forward indeterminately and finally happens in heart failure [ 3 ]. Though fibrosis is a firstly positive course of healing, continuing addition of collagen fibers conducts to constant tissue renovation and substantial organ damage [ 5 ].…”