**2. Molecular mechanisms and pathogenesis of NAFLD**

It is essential to understand the processes that lead to NAFLD and NASH development. Even with the current advancement, our understanding of the pathogenesis of NAFLD is still lacking. The initial theory for the pathophysiology of NAFLD was based on two hypotheses. The first hypothesis described the accumulation of hepatic triglycerides which makes the liver more vulnerable to injury, mediated by the second hypothesis, such as inflammatory cytokines and adipokines, mitochondrial dysfunction, and oxidative stress, which in turn cause steatohepatitis and fibrosis. Also, an increased influx of free fatty acids (FFA) to the liver has been observed in IR and obesity. This concept, however, has been altered as FFA is increasingly understood to play a direct role in triggering liver injury [4, 6, 7]. The FFA can also promote hepatic lipid accumulation either through β-oxidation or esterified with glycerol to form triglycerides. Since convincing evidence has suggested that FFA can trigger inflammatory pathways by facilitating oxidative stress, hepatic triglyceride formation may serve as a defensive

*Non-Alcoholic Fatty Liver Disease: Pathogenesis and the Significance of High-Density… DOI: http://dx.doi.org/10.5772/intechopen.108199*

#### **Figure 1.**

*Molecular mechanisms of NAFLD progression. Lipid accumulation and and high cholesterol levels can lead to alterations in intestinal flora, insulin resistance, and adipocyte proliferation. Free fatty acid and free cholesterol consumption leads to ER stress, oxidative stress, hepatic inflammation, and fibrogenesis, which promotes the development of NAFLD. Adipocytes secrete adipokines including IL-6 and TNF, which have an impact on the liver inflammatory environment and hepatocyte fat accumulation. Macrophages are crucial in the development of inflammation and insulin resistance. Recent study has recognized the gut microbiome as being associated with the development of NAFLD. The pattern of microbiome diversity can facilitate intestinal mucosal permeability and lead to lipopolysaccharidaemia, which is correlated with the development of NAFLD and NASH. Lipoprotein lipase (LPL) activity and triglyceride accumulation are both increased when enteric bacteria inhibit the secretion of adipocyte factor.*

mechanism to counteract the harmful effects of unesterified FFA. In a healthy liver, apoptotic cells prompt mature hepatocytes to multiply, replacing the dead cells and re-establishing normal tissue function [4]. However, oxidative stress, a key factor in the development of NAFLD, prevents mature hepatocytes from replicating, which causes the population of hepatic progenitor cells to increase. The hepatic progenitor cells can differentiate into hepatocyte-like cells, and together with intermediate hepatocyte-like cells, can have numbers that are strongly correlated with the fibrosis stage, signifying that cumulative hepatocyte loss stimulates both the deposition of progenitor cells and their differentiation into hepatocytes. Hepatocellular carcinogenesis has also been linked to the activation of these cells. Since the effectiveness of hepatocyte regeneration is required for the fibrosis and cirrhosis that results from chronic liver injury, cell death with impaired hepatocyte progenitor proliferation is thought to be the "third hypothesis" in the pathogenesis of NAFLD [4]. Several factors, including oxidative stress, insulin resistance, steatohepatitis, endoplasmic reticulum stress, bacterial overgrowth, fibrosis, genetic implications, immune system, and beverages consumption, have been implicated in the progress of NAFLD (**Figure 1**) [4].
