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Review
. 2020 May 29;21(11):3863.
doi: 10.3390/ijms21113863.

The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease

Hideki Fujii  1 , Norifumi Kawada  2 , Japan Study Group Of Nafld Jsg-Nafld
Affiliations
Review

The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease

Hideki Fujii et al. Int J Mol Sci. .

Abstract

Nonalcoholic fatty liver disease (NAFLD) consists of the entire spectrum of fatty liver disease in patients without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis, with NASH recently shown as an important cause of hepatocellular carcinoma (HCC). There is a close relationship between insulin resistance (IR) and NAFLD, with a five-fold higher prevalence of NAFLD in patients with type 2 diabetes (T2DM) compared to that in patients without T2DM. IR is involved in the progression of disease conditions such as steatosis and NASH, as well as hepatic fibrosis progression. The mechanisms underlying these processes involve genetic factors, hepatic fat accumulation, alterations in energy metabolism, and inflammatory signals derived from various cell types including immune cells. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell (HSC). HSC activation by IR involves "direct" and "indirect" pathways. This review will describe the molecular mechanisms of inflammation and hepatic fibrosis in IR, the relationship between T2DM and hepatic fibrosis, and the relationship between T2DM and HCC in patients with NAFLD.

Keywords: hepatic fibrosis; hepatocellular carcinoma; inflammation; insulin resistance; stellate cell.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Summary of inflammatory pathways affecting hepatic insulin resistance (IR) in nonalcoholic fatty liver disease (NAFLD). Insulin activates its receptor, which results in tyrosine phosphorylation on the insulin receptor substrate (IRS1 and IRS2) and activation of downstream effector pathways, including the phosphatidylinositol 3-kinase (PI3K)-phosphoinositide-dependent kinase (PDK)-protein kinase B (AKT) and the RAS−extracellular-signal-regulated kinase (ERK) pathways (i.e., canonical IRS signaling). Numerous pro-inflammatory signaling or reactive oxygen species can activate IKK-β. The activated NF-kB is then translocated into the nucleus and binds to specific DNA response elements. Inflammatory cytokines such as IL-6 promote IR by inducing suppressor of cytokine signaling (SOCS) 1 and 3. SOCS1 and SOCS3 impair insulin signaling through ubiquitin-dependent degradation of IRS. The c-Jun N-terminal kinase (JNK, or mitogen-activated protein kinase) represents another important inhibitory kinase of IRS that is activated in response to a variety of extracellular stimuli and cellular stressors such as oxidative and endoplasmic reticulum (ER) stress.
Figure 2
Figure 2
The indirect pathways regulating hepatic stellate cell (HSC) activation in steatohepatitis. Metabolic insults such as hyperinsulinemia/hyperglycemia lead to the activation of transcriptional coactivator with PDZ-binding motif (TAZ) in hepatocytes. Increased hepatocyte expression of TAZ in nonalcoholic steatohepatitis (NASH) but not simple steatosis directly leads to HSC activation through the release of Indian hedgehog (Ihh) and promotes hepatocyte injury and inflammation that may indirectly promote HSC activation. Notch activation by cell-surface ligands on a neighboring cell leads to a Sox9-dependent increase in osteopontin (OPN) secretion to activate HSCs. HSC activation occurs through direct interactions between stressed or dead hepatocytes (i.e., apoptosis, necrosis, or necroptosis) and HSCs. This may be through the release of profibrogenic damage-associated molecular patterns. High mobility group box 1 (HMGB1) is released by injured hepatocytes to mediate the recruitment of neutrophils. Monocyte infiltration into the liver is primarily controlled by C–C chemokine receptors (CCR2) and its ligand CCL2, which may serve as therapeutic _targets in NASH. Adiponectin modulates Kupffer cell function via reduction of Toll-like receptor 4 (TLR4) signaling, and directly stimulates M1→M2 polarization.
Figure 3
Figure 3
The direct pathways regulating HSC activation in steatohepatitis. Hyperinsulinemia can directly stimulate HSCs to proliferate and secrete type I collagen by differentially activating PI3K- and ERK-dependent pathways. IGF1R triggers ERK1/2 phosphorylation via IRS2, leading to the expression of matrix metalloproteinase (MMP)-9. Hyperglycemia can aggravate hepatic fibrosis, which may be associated with the HSC autophagy induced by acid-sensing ion channel 1a (ASIC1a).
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