Mechanisms and disease consequences of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma. Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell activation, and consider the role of genetic, epigenetic, and environmental factors that promote fibrosis progression and risk of hepatocellular carcinoma in NASH.

Keywords: fibrosis; insulin resistance; lipotoxicity; liver cancer; metabolism-associated fatty liver disease; nonalcoholic steatohepatitis.

Figure 1.. Histologic difference between NAFLD and NASH

Shown is the liver histology of NAFLD with an example of an individual with nonalcoholic fatty liver (NAFL), the non-progressive form of NAFLD, showing macrovesicular steatosis and mild lobular inflammation but no ballooning, and nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, showing ballooned hepatocytes (arrows) in addition to steatosis and lobular inflammation.

Figure 2.. Natural history of NAFLD

NAFLD afflicts up to 80 million Americans, and its progressive form, NASH, affects approximately 20% of individuals with NAFLD. People with NASH are at a high risk of developing liver fibrosis, and a small fraction, approximately 15%, develop cirrhosis. Individuals with NASH cirrhosis are at increased risk of developing HCC and require HCC screening and surveillance; they are at increased risk of liver decompensation and may require liver transplantation. The risk of liver-related mortality is increased significantly in individuals with cirrhosis. Overall, among people with NAFLD, cardiovascular disease is the leading cause of death, followed by cancer and liver-related death.

Figure 3.. Metabolic causes of NAFLD

Increased energy intake, particularly with a Western diet rich in sucrose, high-fructose corn syrup, and saturated fat, leads to NAFLD and increased ectopic lipid deposition in skeletal muscle. Increases in intramyocellular lipid content, which typically occurs prior to onset of NAFLD, causes muscle insulin resistance, resulting in inhibition of insulin signaling and decreased insulin-stimulated glucose transport and muscle glycogen synthesis. Because ingested glucose cannot be stored properly as muscle glycogen, it is redirected to the liver, where, in combination with compensatory portal vein hyperinsulinemia because of muscle insulin resistance, it stimulates SREBP1c, which, in turn, promotes increased expression of key hepatic enzymes that regulate DNL, resulting in increased VLDL production, hypertriglyceridemia, and NAFLD. Monosaccharides can also promote development of NAFLD by recruiting other transcription factors, including ChREBP, PPARγ coactivator 1-β, and LXR to activate hepatic lipogenesis. WAT insulin resistance and/or WAT inflammation results in increased rates of lipolysis and increased fatty acid delivery to the liver, which promotes increased fatty acid esterification into hepatic triglycerides and NAFLD in a substrate-dependent and mostly insulin-independent manner. Triglyceride rich lipoproteins (TRLs) are cleared from the circulation by peripheral lipoprotein lipase (Lpl) activity. Endogenous Lpl inhibitors (e.g. ApoC3, ANGPTL3/8 complex, and ANGPTL4) attenuate peripheral triglyceride clearance, increasing hepatic triglyceride uptake from TRLs (e.g. chylomicron remnants). Reduced fat mass because of acquired and congenital forms of lipodystrophy/partial lipodystrophy also result in increased ectopic lipid storage in the liver and skeletal muscle because of lipid spillover from WAT to the liver. Other metabolic causes of NAFLD and NASH, which are most often genetically related, include (1) defects in intrahepatic lipolysis (e.g., decreased ATGL/CGI-58 activity); (2) defects in triglyceride export (e.g., defective Apo-B 100, MTTP activity); (3) increased glucokinase activity, resulting in increased hepatic DNL; and (4) reductions in hepatic mitochondrial/peroxisomal β-oxidation. Other genetic causes that confer an increased risk (PNPLA3, TM6SF2, and MBOAT7) or decreased risk (HSD17B13) of NAFLD are also likely to be linked metabolically through unknown mechanisms.

Figure 4.. A gene-environment nexus drives the risk of cirrhosis and HCC in NASH

The PNPLA3 gene is a major driver of NAFLD, NASH, cirrhosis, and HCC risk in individuals who have metabolic risk factors such as obesity, diabetes, and metabolic syndrome. Other genetic factors are also involved in NASH progression. Most genetic factors manifest in the setting of metabolic risk factors, including obesity, diabetes, and metabolic syndrome, as well as other environmental factors, such as alcohol and smoking. The gut microbiome is altered by diet and alcohol and in concert with changes in bile acid and metabolic dysfunction, including lipotoxicity. These alteration promote disease progression to cirrhosis and HCC in a susceptible host. Therefore, gene-environment interaction drives the risk of NASH cirrhosis and HCC.

Figure 5.. Cellular and signaling events in NASH

NASH results from a cascade of cellular and signaling events that begin with external stimuli derived from visceral adipose tissue and the gut microbiome as well as inflammatory and immune cells. These inputs converge on hepatocytes to generate a range of intracellular responses, including activation of nuclear receptors (FXR, LXR, PXR, and vitamin D receptor), altered insulin signaling, mitochondrial dysfunction, and lipogenesis. Genetic variants in PNPLA3, HSD17B13, and others may influence the propensity for cell injury and liberation of proinflammatory and fibrogenic signals. Hepatic stellate cells are activated by these signals and undergo a series of intracellular responses that culminate in enhanced extracellular matrix (e.g., collagen) production. It is not certain whether these events characterize every individual with NASH and fibrosis or whether there are endophenotypes of disease that engage different mediators and cells to yield a similar histologic picture. It is also not known which events or signals represent the most critical points of therapeutic vulnerability.