From fatty liver to fibrosis:A tale of “second hit”

Although much is known about how fat accumulates in the liver,much remains unknown about how this causes sustained hepatocellular injury.The consequences of injury are recognized as nonalcoholic steatohepatitis(NASH) and progressive fibrosis.The accumulation of fat within the hepatocytes sensitizes the liver to injury from a variety of causes and the regenerative capacity of a fatty liver is impaired.An additional stressor is sometimes referred to as a "second hit" in a paradigm that identifies the accumulation of fat as the "first hit".Possible candidates for the second hit include increased oxidative stress,lipid peroxidation and release of toxic products such as malondialdehyde and 4-hydroxynonenal,decreased antioxidants,adipocytokines,transforming growth factor(TGF)-β,Fas ligand,mitochondrial dysfunction,fatty acid oxidation by CYPs(CYP 2E1,4A10 and 4A14),and peroxisomes,excess iron,small intestinal bacterial overgrowth,and the generation of gut-derived toxins such as lipopolysaccharide and ethanol.Oxidative stress is one of the most popular proposed mechanisms of hepatocellular injury.Previous studies have specifically observed increased plasma and tissue levels of oxidative stress markers and lipid peroxidation products,with reduced hepatic and plasma levels of antioxidants.There is also some indirect evidence of the benefit of antioxidants such as vitamin E,S-adenosylmethionine,betaine,phlebotomy to remove iron,and N-acetylcysteine in NASH.However,a causal relationship or a pathogenic link between NASH and oxidative stress has not been established so far.A number of sources of increased reactive oxygen species production have been established in NASH that include proinflammatory cytokines such as tumor necrosis factor(TNF)-α,iron overload,overburdened and dysfunctional mitochondria,CYPs,and peroxisomes.Briefly,the pathogenesis of NASH is multifactorial and excess intracellular fatty acids,oxidant stress,ATP depletion,and mitochondrial dysfunction are important causes of hepatocellular injury in the steatotic liver.

Fructose as a key player in the development of fatty liver disease

We aimed to investigate whether increased consumption of fructose is linked to the increased prevalence of fatty liver.The prevalence of nonalcoholic steatohepatitis(NASH) is 3% and 20% in nonobese and obese subjects,respectively.Obesity is a low-grade chronic inflam-m-atory condition and obesity-related cytokines such as interleukin-6,adiponectin,leptin,and tumor necrosis factor-α may play important roles in the developm-ent of nonalcoholic fatty liver disease(NAFLD).Additionally,the prevalence of NASH associated with both cirrhosis and hepatocellular carcinom-a was reported to be high am-ong patients with type 2 diabetes with or without obesity.Our research group previously showed that consumption of fructose is associated with adverse alterations of plasma lipid profiles and metabolic changes in m-ice,the Am-erican Lifestyle-Induced Obesity Syndrom-e m-odel,which included consum-ption of a high-fructose corn syrup in amounts relevant to that consum-ed by som-e Am-ericans.The observation reinforces the concerns about the role of fructose in the obesity epidem-ic.Increased availability of fructose(e.g.,high-fructose corn syrup) increases not only abnorm-al glucose flux but also fructose m-etabolism-in the hepatocyte.Thus,the anatomic position of the liver places it in a strategic buffering position for absorbed carbohydrates and am-ino acids.Fructose was previously accepted as a beneficial dietary com-ponent because it does not stim-ulate insulin secretion.However,since insulin signaling plays an important role in central m-echanism-s of NAFLD,this property of fructose m-ay be undesirable.Fructose has a selective hepatic m-etabolism,and provokes a hepatic stress response involving activation of c-Jun N-term-inal kinases and subsequent reduced hepatic insulin signaling.As high fat diet alone produces obesity,insulin resistance,and som-e degree of fatty liver with m-inim-al inflam-m-ation and no fibrosis,the fast food diet which includes fructose and fats produces a gene expression signature of increased hepatic fibrosis,inflam-m-ation,endoplasm-ic reticulumstress and lipoapoptosis.Hepatic de novo lipogenesis(fatty acid and triglyceride synthesis) is increased in patients with NAFLD.Stable-isotope studies showed that increased de novo lipogenesis(DNL) in patients with NAFLD contributed to fat accum-ulation in the liver and the developm-ent of NAFLD.Specifically,DNL was responsible for 26% of accum-ulated hepatic triglycerides and 15%-23% of secreted very low-density lipoprotein triglycerides in patients with NAFLD com-pared to an estim-ated less than 5% DNL in healthy subjects and 10% DNL in obese people with hyperinsulinem-ia.In conclusion,understanding the underlying causes of NAFLD form-s the basis for rational preventive and treatm-ent strategies of this m-ajor form-of chronic liver disease.