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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice
Ying Xia1, Emma Andersson1, Mara Caputo1
1Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Objective:
Non-alcoholic fatty liver disease (NAFLD), the primary hepatic consequence of obesity, is affecting about 25% of the global adult population. The aim of this study was to examine the in vivo role of STE20-type protein kinase TAOK3, which has been previously reported to regulate hepatocellular lipotoxicity in vitro, in the development of NAFLD and systemic insulin resistance in the context of obesity.
Methods:
Taok3 knockout mice and wild-type littermates were challenged with a high-fat diet. Various in vivo tests were performed to characterize the whole-body metabolism. NAFLD progression in the liver, and lipotoxic damage in adipose tissue, kidney, and skeletal muscle were compared between the genotypes by histological assessment, immunofluorescence microscopy, protein and gene expression profiling, and biochemical assays. Intracellular lipid accumulation and oxidative/ER stress were analyzed in cultured human and mouse hepatocytes where TAOK3 was knocked down by small interfering RNA. The expression of TAOK3-related STE20-type kinases was quantified in different organs from high-fat diet-fed Taok3-/- and wild-type mice.
Results:
TAOK3 deficiency had no impact on body weight or composition, food consumption, locomotor activity, or systemic glucose or insulin homeostasis in obese mice. Consistently, Taok3-/- mice and wild-type littermates developed a similar degree of high-fat diet-induced liver steatosis, inflammation, and fibrosis, and we detected no difference in lipotoxic damage of adipose tissue, kidney, or skeletal muscle when comparing the two genotypes. In contrast, the silencing of TAOK3 in vitro markedly suppressed ectopic lipid accumulation and metabolic stress in mouse and human hepatocytes. Interestingly, the hepatic mRNA abundance of several TAOK3-related kinases, which have been previously implicated to increase the risk of NAFLD susceptibility, was significantly elevated in Taok3-/- vs. wild-type mice.
Conclusions:
In contrast to the in vitro observations, genetic deficiency of TAOK3 in mice failed to mitigate the detrimental metabolic consequences of chronic exposure to dietary lipids, which may be partly attributable to the activation of liver-specific compensation response for the genetic loss of TAOK3 by related STE20-type kinases.
Insights
Genetic deficiency of TAOK3 did not prevent non-alcoholic fatty liver disease (NAFLD) in mice, despite in vitro findings. Related kinases may compensate for TAOK3 loss in vivo.
Area of Science:
- Metabolic diseases
- Hepatology
- Molecular biology
Background:
- Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults globally, linked to obesity.
- Hepatocellular lipotoxicity is a key factor in NAFLD development.
- TAOK3 kinase was previously shown to regulate lipotoxicity in vitro.
Purpose of the Study:
- To investigate the in vivo role of TAOK3 in NAFLD and insulin resistance in obese mice.
- To determine if TAOK3 deficiency impacts metabolic consequences of a high-fat diet.
Main Methods:
- Used Taok3 knockout and wild-type mice fed a high-fat diet.
- Assessed whole-body metabolism, liver NAFLD progression, and lipotoxic damage in multiple organs.
- Analyzed lipid accumulation and stress in cultured hepatocytes with TAOK3 knockdown.
Main Results:
- TAOK3 deficiency did not alter body weight, composition, or systemic glucose/insulin homeostasis.
- No significant differences in diet-induced liver steatosis, inflammation, fibrosis, or organ lipotoxicity between genotypes.
- TAOK3 knockdown in vitro suppressed lipid accumulation and metabolic stress in hepatocytes.
Conclusions:
- In vivo genetic TAOK3 deficiency did not protect against diet-induced NAFLD or metabolic dysfunction.
- Liver-specific compensatory activation of related STE20-type kinases may explain the lack of in vivo effect.
- In vitro findings on TAOK3's role in lipotoxicity do not fully translate to the in vivo obese context.
