Non-alcoholic fatty liver disease severity is modulated by transglutaminase type 2

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most important liver diseases worldwide. Currently, no effective treatment is available, and NAFLD pathogenesis is incompletely understood. Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose dysregulation is implicated in the pathogenesis of various human diseases. Here we examined the impact of TG2 on NAFLD progression using the high-fat-diet-induced model in both wild-type and TG2-deficient mice. Animals were fed with a standard chow diet or a high-fat diet (42% of the energy from fat) for 16 weeks. Results demonstrated that the absence of a functional enzyme, which causes the impairment of autophagy/mitophagy, leads to worsening of disease progression. Data were confirmed by pharmacological inhibition of TG2 in WT animals. In addition, the analysis of human liver samples from NAFLD patients validated the enzyme’s involvement in the liver fat disease pathogenesis. Our findings strongly suggest that TG2 activation may offer protection in the context of NAFLD, thus representing a novel therapeutic target for tackling the NAFLD progression.

Prohibitin 2 deficiency impairs cardiac fatty acid oxidation and causes heart failure

“…In addition, accumulating evidences show that autophagy is critical in metabolic homeostasis maintenance, protein quality control and mitochondrial network remodeling, which offers autophagy as an emerging target for treating cardiorenal metabolic disease 4 . Here, as PHB2 is an inner mitochondrial membrane mitophagy receptor 14 and autophagy is reported to be involved in disturbed lipid metabolism [44][45][46] , the roles of PHB2 on cardiac autophagy in heart failure or other cardiac pathologies should be further investigated in future studies.…”

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…The observed structural changes indicate increased fission of mitochondria, and upregulation of fission proteins in the livers of HF diet-fed animals has been observed in several studies [159,218,220,221]. Ultrastructural electron microscopy (EM) analysis also revealed increased mitochondrial fission in the livers of HF diet-fed animals [220]. A blockade of mitochondrial fission by inducible ablation of DRP1 led to a massive reduction in HF diet-induced steatosis, liver damage and oxidative stress [221].…”

“…Interestingly, one study showed the complete absence of mitochondrial changes under a HF diet when animals were forced to undergo regular endurance training [219]. The observed structural changes indicate increased fission of mitochondria, and upregulation of fission proteins in the livers of HF diet-fed animals has been observed in several studies [159,218,220,221]. Ultrastructural electron microscopy (EM) analysis also revealed increased mitochondrial fission in the livers of HF diet-fed animals [220].…”

Prevention of arachidonic acid‑induced liver injury by controlling oxidative stress‑mediated transglutaminase activation with garlic extracts

“…5). Opposing roles of TG2 in the onset of liver injury have been reported due to its dual function in the regulation of cell survival and death (15,29,30). Extracellular and cytoplasmic TG2 in the closed form exhibit multiple functions, such as GTPase, cell adhesion and scaffold activities, which are associated with cell growth and may prevent liver injury by favoring tissue stability (31).…”