Cold exposure‐induced endoplasmic reticulum stress regulates autophagy through the SIRT2/FoxO1 signaling pathway

Abstract

Cold is a factor affecting health in humans and animals. The liver, a major metabolic center, is highly susceptible to ambient air temperature. Recent studies have shown that endoplasmic reticulum (ER) stress is associated with the liver, and regulates the occurrence and development of liver injury and autophagy. However, the mechanism underlying the relationship between cold exposure and ER stress in the liver is not well understood. In this study, we investigated the effect of ER stress on liver autophagy and its mechanism under cold exposure. AML12 cells were treated with Tg to construct an ER stress model, and the level of autophagy increased. To further explore the mechanism through which ER stress regulates autophagy, we knocked down SIRT2 with shRNA in Tg‐treated AML12 cells. Knockdown of SIRT2 significantly increased ER stress and autophagy, increased FoxO1 acetylation, and promoted its entry into the nucleus. To further verify the results of in vitro experiments, we exposed mice to 4°C for 3 h per day for 3 weeks to exacerbate the burden on the liver after cold exposure. Cold exposure damaged the structure and function of the liver and promoted the inflammatory response. It also activated ER stress and promoted autophagy. In addition, cold exposure inhibited the expression of SIRT2, promoted FoxO1 acetylation, and enhanced the interaction with autophagy. Our findings indicated that cold exposure induces liver damage, ER stress, and autophagy through the SIRT2/FoxO1 pathway. These findings suggest that SIRT2 may be a potential target for regulating health under cold exposure.

Sirtuins and autophagy in lipid metabolism

“…56 Cold exposure activates endoplasmic reticulum stress in the liver and promotes autophagy, which is produced by affecting SIRT2 expression and activity and thereby altering FOXO1 acetylation levels. 57 More studies suggest that SIRT3 is a positive regulator of autophagy. In mature adipocytes, the overexpression of SIRT3 activates macroautophagy by activating AMPK-ULK1 pathway, mainly on LDs, which can lead to the reduction of LD size and lipid accumulation.…”

“…SIRT2 also plays a role in the dysregulation of autophagy in innate immune cells, and several key autophagy regulators, such as LC3b‐II, p62 and α‐microtubulin, were found to interact directly with SIRT2 and beclin‐1 indirectly with SIRT2 in the in vitro LPS‐induced cell model of RAW macrophages 56 . Cold exposure activates endoplasmic reticulum stress in the liver and promotes autophagy, which is produced by affecting SIRT2 expression and activity and thereby altering FOXO1 acetylation levels 57 …”

Strategies for the Management of Spike Protein-Related Pathology

“…Resveratrol can also induce fasting, as it acts as a protein restriction mimetic 134 , and metformin, a diabetes medication, can influence autophagy signalling 135 . Surpisingly, cold exposure, in addition to heat exposure, also increases autophagy 136,137 . Hyperbaric oxygen 138 and ozone therapy 139 may also stimulate autophagy.…”

Strategies for the Management of Spike Protein-Related Pathology

“…Resveratrol can also induce fasting, as it acts as a protein restriction mimetic [145], and metformin, a diabetes medication, can influence autophagy signalling [146]. Surprisingly, cold exposure, in addition to heat exposure, also increases autophagy [147,148]. Hyperbaric oxygen [149] and ozone therapy [150] may also stimulate autophagy.…”