Inflammation initiates a vicious cycle between obesity and nonalcoholic fatty liver disease

Abstract

Low-level of chronic inflammation activation is characteristic of obesity. Nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity and is an emerging health problem, it originates from abnormal accumulation of triglycerides in the liver, and sometimes causes inflammatory reactions that could contribute to cirrhosis and liver cancer, thus its pathogenesis needs to be clarified for more treatment options. Once NAFLD is established, it contributes to systemic inflammation, the low-grade inflammation is continuously maintained during NAFLD causing impaired resolution of inflammation in obesity, which subsequently exacerbates its severity. This study focuses on the effects of obesity-induced inflammations, which are the underlying causes of the disease progression and development of more severe inflammatory and fibrotic stages. Understanding the relationship between obesity and NAFLD could help in establishing attractive therapeutic targets or diagnostic markers in obesity-induced inflammation response and provides new approaches for the prevention and treatment of NAFLD in obesity.

Keywords: NAFLD; adipose tissue inflammation; obesity; obesity-induced inflammation.

Figure 1

The relationship between obesity‐induced adipose tissue inflammation and NAFLD. Obesity changes the composition of immune cells in adipose tissue, thereby disrupting energy storage or consumption. This in turn triggers inflammation of adipose tissue, and the death of adipocytes further aggravating obesity. Inflammation of adipose tissue, resulting in secretion of factors (known as adipokines), increases generation of FFA and infiltration of M1 macrophages in the liver, as well as insulin resistance. Together, they influence the progression of NAFLD, leading to steatosis, liver inflammation and fibrosis, cirrhosis, and even increased risk of hepatocellular carcinoma. Systemic insulin resistance due to cirrhosis can exacerbate the inflammatory state of adipose tissue by reducing its energy storage capacity. FFA, free fatty acid; NAFLD, nonalcoholic fatty liver disease

Figure 2

Relationship between obesity‐related vascular inflammatory factors and NAFLD. Blood levels of immune mediators (such as CRP, IL‐6, and CCL2), white blood cell, and TH1, TH17 cell numbers increase with the severity of obesity, contributing to the development of NAFLD. Excessive secretion of Fetuin‐A from liver in NAFLD patients activates TLR4 signaling, which impairs insulin receptor signaling and promotes the release of pro‐inflammatory cytokines. Serum factors such as the AST/ALT or AA/EPA ratio can reflect the progression and severity of obesity and NAFLD. AA/EPA, arachidonic acid/eicosapentaenoic acid; AST/ALT, aspartate aminotransferase/alanine aminotransferase; CRP, C‐reactive protein (CRP); CCL2, CC chemokine ligand 2; IL‐6, interleukin 6; NAFLD, nonalcoholic fatty liver disease; TLR4, Toll‐like receptor4

Figure 3

The relationship between obesity‐induced intestinal inflammation and NAFLD. Obesity has been linked to changes in the composition of the human intestinal microbiota. Mechanistically, it activates inflammatory pathways in the gut, thereby changing the intestinal microbiota composition, this process can affect obesity and pro‐inflammatory status. Chronic inflammation in the intestines induces liver toxicity due to gut‐derived toxic products, such as LPS. These products trigger NAFLD by activating the pathway of immune and inflammatory responses, as well as other downstream TLR4, IRAK, JNK, and IKK complexes. Inflammation increases the severity of liver inflammation by enhancing intestinal permeability. Liver damage in nonalcoholic steatohepatitis further increases intestinal permeability and exacerbates intestinal inflammation. The use of prebiotics (which promote the growth of good intestinal flora) and probiotics (living microorganisms) in the gut flora can be beneficial for ameliorating both NAFLD and intestinal inflammation. IKK, I‐kappa B kinase; IRAK, interleukin‐1 receptor associates kinase; JNK, C‐Jun N‐terminal kinase; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; TLR4, toll‐like receptor 4

Figure 4

The relationship between obesity‐induced skeletal muscle inflammation and NAFLD. Obesity leads to ectopic lipid accumulation in skeletal muscle and triggers inflammatory response by decreasing skeletal muscle mass, aggravate insulin resistance, upregulating pro‐inflammatory cytokines (e.g., TNF‐α), and downregulating adipokines (e.g., leptin, and adiponectin), all of which contribute to the onset and progression of NAFLD. Inflammation of skeletal muscle decreases insulin sensitivity, thereby modifying obesity and the development of associated NAFLD; conversely, NAFLD as well as alters the factors (e.g., LECT2 and hepassocin) secreted by the liver, further promotes skeletal muscle insulin resistance and exacerbate the inflammatory response in skeletal muscle. LECT2, leukocyte cell‐derived chemotaxin 2; NAFLD, nonalcoholic fatty liver disease; TNF‐α, tumor necrosis factor‐α

Figure 5

The relationship between obesity‐induced brain tissue inflammation and NAFLD. Overnutrition caused by obesity activates NF‐κB, pro‐inflammatory cytokines, PKC‐θ and other signaling pathways in the brain. Following inflammation of the brain tissue, endoplasmic reticulum stress occurs, AST/ALT increases, and LPS stimulates TLR4 signals, ghrelin induces insulin resistance and promotes liver lipid accumulation. The progress of NAFLD is also accompanied by an increased inflammatory cytokines profile in the brain, at the same time, the metabolism of cholesterol and fatty acids in the brain is unbalanced, which further aggravates the brain tissue inflammation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ER, endoplasmic reticulum; iNOS, inducible nitric oxide synthase; IR, insulin resistance; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; NF‐κB, nuclear factor‐κB; PKC‐θ, protein kinase C‐θ; ROS, reactive oxygen species

Figure 6

The role of obesity‐induced inflammation in nonalcoholic fatty liver disease (NAFLD). Obesity plays a role in the development of associated NAFLD by affecting several inflammatory reactions via adipose tissue, vascular, intestinal, skeletal muscle and brain, this process is associated with adipose tissue inflammation, inflammatory factors in the blood, intestinal inflammation, skeletal muscle inflammation and brain tissue inflammation. Obesity and NAFLD are the net effects of these changes. Once NAFLD has been established, it contributes to systemic inflammation, and the low‐grade inflammation is sustained during NAFLD leading to impaired resolution of inflammation in obesity, which subsequently can in turn exacerbates the severity of obesity. SM, skeletal muscle