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Role of Autophagy and Peroxisome Proliferator-Activated Receptor Gamma2 in Hepatic Lipid Homeostasis

Donna Marie Conlon

Title:
Role of Autophagy and Peroxisome Proliferator-Activated Receptor Gamma2 in Hepatic Lipid Homeostasis
Author(s):
Conlon, Donna Marie
Thesis Advisor(s):
Ginsberg, Henry N.
Date:
Type:
Theses
Degree:
Ph.D., Columbia University
Department(s):
Nutritional and Metabolic Biology
Persistent URL:
Abstract:
The liver maintains lipid homeostasis by regulating hepatic uptake of circulating fatty acids (FA) and triglycerides (TG), de novo lipogenesis (DNL), FA, and secretion of TG in very low density lipoproteins (VLDL). To investigate the effects of reduced VLDL secretion on hepatic lipid homeostasis, we examined the effects of knockdown of either apolipoproteinB (apoB) or microsomal triglyceride transfer protein (MTP) using antisense oligonucleotides (ASO) for 6 weeks in apobec-1 knockout mice. Despite a similar decrease in VLDL secretion in mice treated with either apoB ASO or MTP ASO, there was an increase in liver TG content only in the MTP ASO-treated mice. There were no differences in either FA uptake or secretion, or lipid synthesis from DNL. However, there was an increase in autophagosomes that co-localized with the endoplasmic reticulum (ER) in the apoB ASO-treated livers. We hypothesized that there is an accumulation of lipid in the ER due to the absence of apoB, the necessary protein for the formation and secretion of VLDL, and so the lipid becomes trapped inside the lumen of the ER. We provide evidence that the ER was engulfed by autophagosome and shuttled to the lysosome where the ER and its lipid content were degraded, leading to an increase in FA oxidation. This increase in autophagy of the ER prevented steatosis. We were surprised, however, that there was no evidence for ER stress after 6 weeks of knockdown of apoB and so we next examined the effect of only 3 weeks of ASO treatment and found that at this earlier time point, apoB ASO-treated mice had increased steatosis as compared to control ASO-treated mice and that the level of steatosis was similar to that caused by MTP ASO-treated mice. Furthermore, at 3 weeks of apoB ASO treatment, there was an increase in markers of ER stress in the apoB ASO-treated mice, but no evidence of an increase in the autophagy. After inhibition of autophagy, both ER stress and apoptosis were markedly increased in the livers of the apoB ASO-treated mice, indicating that autophagy protected the hepatocyte when apoB was knocked down. Thus, in this model of inhibition of apoB synthesis, with markedly reduced secretion of VLDL, TG that enters the ER gets trapped there and first induces ER stress. The ER stress response is unable to repair the defect, lipid accumulation in the ER continues to increase, and autophagy of the lipid-filled ER is induced, allowing the lysosome to act as an alternative pathway for oxidation of FA by the mitochondria. Our results suggest, therefore, that by stimulating autophagy, it may be possible to lower plasma TG levels by inhibiting VLDL secretion without causing hepatic steatosis. PPARgamma2, which has been previously shown to contribute to increased lipid accumulation through decreased TG turnover of the lipid droplets and increased DNL, is aberrantly expressed in hepatic steatosis. However, the basis for increased expression of the PPARgamma2 specific isoform in the liver is unknown. We used hepatocytes and in vivo models to study the relative effects of hyperinsulinemia and/or increased FA delivery on hepatic PPARgamma2 and PPARgamma1 expression. Hepatic PPARgamma2 expression is not increased by increased fatty acid delivery in the absence of hyperinsulinemia but is regulated by changes in insulin signaling. Since hyperinsulinemia often occurs in the presence of excess nutrients, including glucose and FA, expression of PPARgamma2 in the liver, with subsequent effects on hepatic lipid droplet formation and stability, may be a means of protecting hepatocytes from lipotoxicity.
Subject(s):
Nutrition
Biology
Item views
182
Metadata:
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Suggested Citation:
Donna Marie Conlon, , Role of Autophagy and Peroxisome Proliferator-Activated Receptor Gamma2 in Hepatic Lipid Homeostasis, Columbia University Academic Commons, .

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