Autophagy Compensates for Lkb1 Loss to Maintain Adult Mice Homeostasis and Survival

Abstract

Liver Kinase B1 (LKB1) is the major energy sensor for cells to respond to metabolic stress. Autophagy degrades and recycles proteins, macromolecules, and organelles for cells to survive starvation. To access the role and cross-talk between autophagy and Lkb1 in normal tissue homeostasis, we generated genetically engineered mouse models where we can conditionally delete Lkb1 and autophagy essential gene, Atg7, respectively or simultaneously, throughout the adult mice. We found that Lkb1 was essential for the survival of adult mice, and autophagy activation could temporarily compensate for the acute loss of Lkb1 and extend mouse life span. We further found that acute deletion of Lkb1 in adult mice led to impaired intestinal barrier function, hypoglycemia, and abnormal serum metabolism, which was partly rescued by the Lkb1 loss-induced autophagy upregulation via inhibiting p53 induction. Taken together, we demonstrated that autophagy and Lkb1 work synergistically to maintain adult mouse homeostasis and survival.

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

“…Studies have shown that LKB1 exerts anti-inflammatory effects by activating AMPK in macrophages to inhibit the production of pro-inflammatory mediators and chemokines (Filippov et al, 2013). Moreover, LKB1 may participate in the regulation of ER stress and autophagy of macrophages through other pathways (Khayati et al, 2020;Zuo et al, 2020). With the deepening of understanding, the pathophysiological value of LKB1 in cardiovascular and metabolic diseases has attracted much attention (Liang et al, 2021;Liu et al, 2021).…”

Autophagy and tumorigenesis

“…Subsequently, induction of p53 activates the transcription of genes involved in autophagy activation or induces autophagy via transcriptional activation of damage-regulated autophagy modulator (DRAM-1) in human and mouse cell lines [94]. On the other hand, in various mouse models, p53 induction was observed when autophagy was ablated, suggesting that autophagy also regulates p53 and may serve as a resistance mechanism against p53 activators [95]. defective FAO and increased sensitivity to FAO inhibition [28,30], 3) p53 induction [28,[95][96][97], and 4) higher basal ROS levels [29].…”

“…Besides tumor-intrinsic autophagy, systemic host autophagy is indispensable for tumorigenesis [27,31]. Systemic ablation of autophagy leads to the depletion of a number of amino acids and other essential metabolites in serum, including leucine, arginine, and methionine, some of which are essential for mTORC1 activation [27,31,95,[114][115][116]. Indeed, acute, systemic deletion of Atg7 or Atg5 impaired tumor growth, which was accompanied by reduced mTOR activity [27,31].…”

“…Interestingly, ablation of the LKB1 causes Kras-driven NSCLC to become much more sensitive to autophagy inhibition compared with LKB1 WT lung tumors [30]. Autophagy temporally compensates for acute systemic LKB1 loss for adult mouse survival [95]. In the case of Kras-driven lung tumors, studies suggest that the loss of LKB1 leads to the reduced metabolic plasticity in response to metabolic stress during tumorigenesis, which is further exaggerated by autophagy ablation, leading to energy crises in the tumor cell [30].…”

“…Fig.5. Autophagy Supports Cancer Cell Metabolism (A) Ablation of cell-autonomous autophagy in tumor cells leads to a variety of outcomes: 1) lowered levels of amino acids, ATP production, and nucleotides synthesis due to reduced substrate recycling[29,89,90], 2) defective FAO and increased sensitivity to FAO inhibition[28,30], 3) p53 induction[28,[95][96][97], and 4) higher basal ROS levels[29]. (B) Ablation of non-cell-autonomous autophagy causes various outcomes in the host and the TME: 1) Ablation of host autophagy or liver autophagy causes the release of arginase I from hepatocytes, thereby reducing circulating arginine that is essential for tumor growth[31], 2) ablation of systemic autophagy also leads to deduced metabolites in the TME, leading to tumor death[31], 3) ablation of systemic autophagy is associated with reduced mTOR activity, impairing tumor growth[27,31], and 4) ablation of autophagy in stromal cells of PDAC restrains the supply of metabolites to tumor cells[33].…”