Adipose tissue insulin resistance exacerbates liver inflammation and fibrosis in a diet-induced NASH model

Abstract

Background: Insulin regulates various biological processes in adipocytes, and adipose tissue dysfunction due to insulin resistance in this tissue plays a central role in the development of metabolic diseases, including NAFLD and NASH. However, the combined impact of adipose tissue insulin resistance and dietary factors on the pathogenesis of NAFLD-NASH has remained unknown. Methods and Results: 3′-phosphoinositide–dependent kinase 1 (PDK1) is a serine-threonine protein kinase that mediates the metabolic actions of insulin. We recently showed that adipocyte-specific PDK1 knockout (A-PDK1KO) mice maintained on normal chow exhibit metabolic disorders, including progressive liver disease leading to NASH, in addition to reduced adipose tissue mass. We here show that maintenance of A-PDK1KO mice on the Gubra amylin NASH (GAN) diet rich in saturated fat, cholesterol, and fructose exacerbates inflammation and fibrosis in the liver. Consistent with these histological findings, RNA-sequencing analysis of the liver showed that the expression of genes related to inflammation and fibrosis was additively upregulated by adipocyte-specific PDK1 ablation and the GAN diet. Of note, the reduced adipose tissue mass of A-PDK1KO mice was not affected by the GAN diet. Our results thus indicate that adipose tissue insulin resistance and the GAN diet additively promote inflammation and fibrosis in the liver of mice. Conclusions: A-PDK1KO mice fed with the GAN diet, constitute a new mouse model for studies of the pathogenesis of NAFLD-NASH, especially that in lean individuals, as well as for the development of potential therapeutic strategies for this disease.

Thrombospondin-1 promotes liver fibrosis by enhancing TGF-β action in hepatic stellate cells

“…Whereas we focused on TSP-1 as a secreted protein whose expression is altered in adipose tissue of our MASH model (A-PDK1KO mice) and we showed that systemic TSP-1 de ciency ameliorates liver brosis in this model, we did not de nitively determine the cell source of the TSP-1 responsible for the promotion of liver brosis. Although TSP-1 is expressed at a higher level in adipose tissue than in the liver 24 , TSP-1 expression is also upregulated in the liver of A-PDK1KO mice 14 as well as in that of patients with chronic liver disease accompanied by brosis 35 . These ndings suggest that TSP-1 derived from certain cell types in the liver as well as that produced by adipocytes may contribute to the pathogenesis of MASH.…”

“…3′-Phosphoinositide-dependent kinase 1 (PDK1) is a serine-threonine kinase that plays a central role in insulin signal transduction by phosphorylating and activating the downstream kinase Akt. We have previously shown that adipocyte-speci c PDK1 knockout (A-PDK1KO) mice manifest a hepatic histology reminiscent of MASH in addition to systemic insulin resistance and related metabolic disorders 6,13,14 .…”