Inflammation: The Straw That Broke the NAFLD Liver!

See rebuttal on page 1275. See counterpoint on page 1267. See rebuttal on page 1275. See counterpoint on page 1267. Nonalcoholic fatty liver disease (NAFLD) is a spectrum of conditions ranging from benign nonalcoholic fatty liver (NAFL) or bland steatosis to the more severe nonalcoholic steatohepatitis (NASH), characterized by excessive inflammation and varying degrees of fibrosis.1Chalasani N. Younossi Z. Lavine J.E. Charlton M. Cusi K. Rinella M. Harrison S.A. Brunt E.M. Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (2813) Google Scholar An estimated 20%–25% of patients with NAFL progress to NASH, and up to 25% of patients with NASH progress to cirrhosis.1Chalasani N. Younossi Z. Lavine J.E. Charlton M. Cusi K. Rinella M. Harrison S.A. Brunt E.M. Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (2813) Google Scholar Currently, NASH-related cirrhosis is the second leading indication for liver transplantation in the United States, and patients with NASH face an increased risk of developing hepatocellular carcinoma.1Chalasani N. Younossi Z. Lavine J.E. Charlton M. Cusi K. Rinella M. Harrison S.A. Brunt E.M. Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (2813) Google Scholar Despite the progress in understanding of the natural history of NAFLD over the last two decades, researchers continue to struggle in identifying the cellular and molecular mechanisms behind the progression of NAFL to NASH and the subsequent development of cirrhosis. In the following, I provide evidence suggesting that steatosis alone is insufficient to drive NAFLD progression, and argue for a multiple-hit model of NASH pathogenesis wherein various host-intrinsic and extrinsic insults promote hepatic inflammation fueling NAFLD progression. NAFL is characterized by accumulation of fatty acids as triacylglycerol in hepatocytes in the absence of inflammation or liver injury.1Chalasani N. Younossi Z. Lavine J.E. Charlton M. Cusi K. Rinella M. Harrison S.A. Brunt E.M. Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (2813) Google Scholar Fat deposition in hepatocytes or hepatosteatosis is observed when hepatic fatty acid uptake and/or synthesis exceeds fatty acid catabolism via fatty acid oxidation and export as very low-density lipoproteins.2Musso G. Gambino R. Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD).Prog Lipid Res. 2009; 48: 1-26Crossref PubMed Scopus (490) Google Scholar Unlike adipocytes, hepatocytes do not store fatty acids under homeostatic conditions. However, with insulin resistance, circulating free fatty acids are elevated because insulin does not sufficiently inhibit adipose tissue lipolysis. This increases fatty acid uptake in the hepatocyte resulting in a net increase in hepatic fatty acid deposition.2Musso G. Gambino R. Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD).Prog Lipid Res. 2009; 48: 1-26Crossref PubMed Scopus (490) Google Scholar Although the precise molecular mechanisms and sequence of events leading to hepatic fatty acid accumulation in NAFLD are not well understood, insulin resistance is considered the primary driver of hepatosteatosis.3Khan R.S. Bril F. Cusi K. Newsome P.N. Modulation of insulin resistance in nonalcoholic fatty liver disease.Hepatology. 2019; 70: 711-724PubMed Google Scholar Hepatic insulin resistance prevents suppression of hepatic glucose production contributing to hyperglycemia, increased compensatory hyperinsulinemia, and fatty acid deposition in hepatocytes by promoting de novo lipogenesis.3Khan R.S. Bril F. Cusi K. Newsome P.N. Modulation of insulin resistance in nonalcoholic fatty liver disease.Hepatology. 2019; 70: 711-724PubMed Google Scholar Hepatosteatosis compromises liver function by disrupting hepatic metabolism and in some instances causing hepatocyte apoptosis, which was deemed instrumental in promoting lipotoxicity-induced hepatic inflammation in NAFLD.3Khan R.S. Bril F. Cusi K. Newsome P.N. Modulation of insulin resistance in nonalcoholic fatty liver disease.Hepatology. 2019; 70: 711-724PubMed Google Scholar But given that apoptosis is a nonlytic, noninflammatory cell death pathway that has limited effects on the surrounding cells, steatosis-induced hepatocyte apoptosis may not substantially impact hepatic inflammation in NAFLD.4Nagata S. Apoptosis and clearance of apoptotic cells.Annu Rev Immunol. 2018; 36: 489-517Crossref PubMed Scopus (387) Google Scholar Evidence from animal studies suggests that fatty acid accumulation in hepatocytes is a mechanism to protect tissues from fatty acid–associated lipotoxicity.5Yamaguchi K. Yang L. McCall S. Huang J. Yu X.X. Pandey S.K. Bhanot S. Monia B.P. Li Y.X. Diehl A.M. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.Hepatology. 2007; 45: 1366-1374Crossref PubMed Scopus (726) Google Scholar Furthermore, animal models of hepatosteatosis where a high-fat diet or leptin deficiency resulted in substantial steatosis but not steatohepatitis suggest that hepatosteatosis may not drive NAFLD progression.6Chitturi S. Farrell G. Frost L. Kriketos A. Lin R. Fung C. Liddle C. Samarasinghe D. George J. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?.Hepatology. 2002; 36: 403-409Crossref PubMed Scopus (310) Google Scholar This was further corroborated by clinical evidence that a large proportion of the population with NAFL, which represents 20%–30% of the general population and as high as 75%–100% of obese individuals, are either slow progressors or nonprogressors.1Chalasani N. Younossi Z. Lavine J.E. Charlton M. Cusi K. Rinella M. Harrison S.A. Brunt E.M. Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (2813) Google Scholar As such, from a clinical perspective, NAFL is considered a benign condition that does not require clinical intervention. Emphasis on the metabolic underpinnings of NAFLD led to the proposal of a sequential "two-hit" model to explain disease progression in patients with NAFLD. The "two-hit" model suggests that hepatic lipid accumulation provides the "first-hit" that sensitizes the liver to a "second-hit" of oxidative stress resulting in hepatic inflammation that fuels the progression of NAFLD. The "two-hit" model emphasized that inflammation is the primary driver of disease progression but fell short in recognizing the importance of environmental factors including diet and gut microbiota and the involvement of extrahepatic tissue in disease progression.7Buzzetti E. Pinzani M. Tsochatzis E.A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).Metabolism. 2016; 65: 1038-1048Abstract Full Text Full Text PDF PubMed Scopus (1267) Google Scholar The current refined models (summarized next), supported by the last two decades of research, suggest that disease progression is a culmination of various host-intrinsic and extrinsic factors that contribute to chronic hepatic inflammation that in turn drive progression of NAFLD.7Buzzetti E. Pinzani M. Tsochatzis E.A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).Metabolism. 2016; 65: 1038-1048Abstract Full Text Full Text PDF PubMed Scopus (1267) Google Scholar New models of NAFLD progression are distinguished by their de-emphasis of lipotoxicity as a primary driver, with greater emphasis on the contribution of interactions among the gut, liver and adipose tissue, reflecting the recognition that NAFLD is a complex and heterogeneous disease.8Cordeiro A. Costa R. Andrade N. Silva C. Canabrava N. Pena M.J. Rodrigues I. Andrade S. Ramalho A. Does adipose tissue inflammation drive the development of non-alcoholic fatty liver disease in obesity?.Clin Res Hepatol Gastroenterol. 2020; 44: 394-402Crossref PubMed Scopus (22) Google Scholar,9Tilg H. Moschen A.R. Roden M. NAFLD and diabetes mellitus.Nat Rev Gastroenterol Hepatol. 2017; 14: 32-42Crossref PubMed Scopus (465) Google Scholar The contribution of adipokines and inflammatory cytokines released by inflamed adipose tissue in promoting insulin resistance and steatosis are now well established.9Tilg H. Moschen A.R. Roden M. NAFLD and diabetes mellitus.Nat Rev Gastroenterol Hepatol. 2017; 14: 32-42Crossref PubMed Scopus (465) Google Scholar However, the mechanisms of adipose tissue inflammation during nutrient excess remain incompletely understood. Studies demonstrating that the components of a western diet activate various inflammatory pathways that in turn foster metabolic derangements provide a direct link between diet and inflammation in metabolic diseases including NAFLD.10Konner A.C. Bruning J.C. Toll-like receptors: linking inflammation to metabolism.Trends Endocrinol Metab. 2011; 22: 16-23Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Further demonstrating the overlap between inflammatory and metabolic pathways, numerous studies document that curbing either inflammation or its source not only reduces hepatic inflammation and fibrosis but also improves steatosis and metabolic syndrome.8Cordeiro A. Costa R. Andrade N. Silva C. Canabrava N. Pena M.J. Rodrigues I. Andrade S. Ramalho A. Does adipose tissue inflammation drive the development of non-alcoholic fatty liver disease in obesity?.Clin Res Hepatol Gastroenterol. 2020; 44: 394-402Crossref PubMed Scopus (22) Google Scholar,9Tilg H. Moschen A.R. Roden M. NAFLD and diabetes mellitus.Nat Rev Gastroenterol Hepatol. 2017; 14: 32-42Crossref PubMed Scopus (465) Google Scholar The role of gut microbiota has recently gained significant attention because of evidence demonstrating their involvement in modulating inflammation and metabolism in NAFLD.11Tripathi A. Debelius J. Brenner D.A. Karin M. Loomba R. Schnabl B. Knight R. The gut-liver axis and the intersection with the microbiome.Nat Rev Gastroenterol Hepatol. 2018; 15: 397-411Crossref PubMed Scopus (483) Google Scholar Germ-free mice or mice treated with antibiotics to reduce gut microbial load do not develop NAFLD when placed on a western diet; this helped establish the critical role of gut microbiota in the pathogenesis of the disease.12Kaden-Volynets V. Basic M. Neumann U. Pretz D. Rings A. Bleich A. Bischoff S.C. Lack of liver steatosis in germ-free mice following hypercaloric diets.Eur J Nutr. 2019; 58: 1933-1945Crossref PubMed Scopus (17) Google Scholar The impact of gut permeability is emerging as another important factor in NAFLD that provides insights into the mechanisms of disease progression in a subset of individuals with NAFL. Both clinical and experimental data suggest that the consequence of diet-induced gut dysbiosis and intestinal epithelial barrier disruption increases translocation of gut microbial products, which promote hepatic inflammation and ultimately disease progression.11Tripathi A. Debelius J. Brenner D.A. Karin M. Loomba R. Schnabl B. Knight R. The gut-liver axis and the intersection with the microbiome.Nat Rev Gastroenterol Hepatol. 2018; 15: 397-411Crossref PubMed Scopus (483) Google Scholar Collectively, these recent advances serve to reinforce the adage "you are what you eat" by demonstrating that inflammatory pathways activated by caloric excess cause metabolic diseases including insulin resistance, type II diabetes, cardiovascular disease, and NASH in susceptible individuals.