Hyperglycemia aggravates acute liver injury by promoting liver‐resident macrophage NLRP3 inflammasome activation via the inhibition of AMPK/mTOR‐mediated autophagy induction

Abstract

Although the detrimental effects of diabetes mellitus/hyperglycemia have been observed in many liver disease models, the function and mechanism of hyperglycemia regulating liver-resident macrophages, Kupffer cells (KCs), in thioacetamide (TAA)-induced liver injury remain largely unknown. In this study, we evaluated the role of hyperglycemia in regulating NOD-like receptor family pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting autophagy induction in KCs in the TAA-induced liver injury model. Type I diabetes/hyperglycemia was induced by streptozotocin treatment. Compared with the control group, hyperglycemic mice exhibited a significant increase in intrahepatic inflammation and liver injury. Enhanced NLRP3 inflammasome activation was detected in KCs from hyperglycemic mice, as shown by increased gene induction and protein levels of NLRP3, cleaved caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain and interleukin-1b, compared with control mice. NLRP3 inhibition by its antagonist CY-09 effectively suppressed inflammasome activation in KCs and attenuated liver injury in hyperglycemic mice. Furthermore, inhibited autophagy activation was revealed by transmission electron microscope detection, decreased LC3B protein expression and p-62 protein degradation in KCs isolated from TAA-stressed hyperglycemic mice. Interestingly, inhibited 5 0 AMP-activated protein kinase (AMPK) but enhanced mammalian target of rapamycin (mTOR) activation was found in KCs from TAA-stressed hyperglycemic mice. AMPK activation by its agonist 5aminoimidazole-4-carboxamide ribonucleotide (AICAR) or mTOR signaling knockdown by small interfering RNA restored autophagy activation, and subsequently, inhibited NLRP3 inflammasome activation in KCs, leading to ultimately reduced TAA-induced liver injury in the hyperglycemic mice. Our findings demonstrated that hyperglycemia aggravated TAA-induced acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via inhibiting AMPK/mTOR-mediated autophagy. This study provided a novel target for prevention of toxin-induced acute liver injury under hyperglycemia.

Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice

“…Accordingly, we noted that doxepin treatment led to increases in serum CRP, IL-1β, and TNF-α levels in our doxepin-treated mice, in parallel with glucose intolerance exacerbation ( Figure S7 ). Alternatively, hyperglycemia contributed to Kupffer cells activating and then secreting proinflammatory cytokines such as TNF-α and IL-6 [ 67 , 68 ]. Higher TNF-α levels lead to liver injury mediated by hepatocellular apoptosis [ 69 ].…”

Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment

“…Inflammasomes are multiprotein complexes that sense danger signals like DAMPs and pathogen-associated molecular patterns (PAMPs) from damaged cells and pathogens (79). There are multiple inflammasomes implicated in liver disorders, but the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome has been studied most extensively (80)(81)(82). The NLRP3 inflammasome is activated in a two-step process.…”

Protective Role of Loranthus regularis against Liver Dysfunction, Inflammation, and Oxidative Stress in Streptozotocin Diabetic Rat Model

“…Studies have found that DM could be considered as a risk factor for nonalcoholic fatty liver disease [ 3 ]. In addition, hyperglycemia was reported to exaggerate acute liver injury through inflammasome activation [ 4 ]. The deficiency of intracellular glucose in hepatic cells during DM results in damaging and necrotic effects, which stimulate apoptotic response [ 5 ].…”