Fibroblast Growth Factor 21 Limits Lipotoxicity by Promoting Hepatic Fatty Acid Activation in Mice on Methionine and Choline-Deficient Diets

Abstract

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a common consequence of human and rodent obesity. Disruptions in lipid metabolism lead to accumulation of triglycerides and fatty acids, which can promote inflammation and fibrosis and lead to nonalcoholic steatohepatitis (NASH). Circulating levels of fibroblast growth factor (FGF)21 increase in patients with NAFLD or NASH, so we assessed the role of FGF21 in the progression of murine fatty liver disease, independent of obesity, caused by methionine and choline deficiency. Methods C57BL/6 wild-type and FGF21-knockout (FGF21-KO) mice were placed on methionine- and choline-deficient (MCD), high-fat, or control diets for 8–16 weeks. Mice were weighed; serum and liver tissues were collected and analyzed for histology, levels of malondialdehyde and liver enzymes, gene expression, and lipid content. Results The MCD diet increased hepatic levels of FGF21 mRNA more than 50-fold and serum levels 16-fold, compared with the control diet. FGF21-KO mice had more severe steatosis, fibrosis, inflammation, and peroxidative damage than wild-type C57BL/6 mice. FGF21-KO mice had reduced hepatic fatty acid activation and β oxidation, resulting in increased levels of free fatty acid. FGF21-KO mice given continuous subcutaneous infusions of FGF21 for 4 weeks while on MCD diets had reduced steatosis and peroxidative damage, compared with mice not receiving FGF21. The expression of genes that regulate inflammation and fibrosis were reduced in FGF21-KO mice given FGF21, similar to those of wild-type mice. Conclusions FGF21 regulates fatty acid activation and oxidation in livers of mice. In the absence of FGF21, accumulation of inactivated fatty acids results in lipotoxic damage and increased steatosis.

A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution

“…The connection between dietary AA supply and metabolism has been largely focused upon restriction or deprivation of the EAAs. For example, single EAA restriction (44,45) or deprivation (46,47) has been associated with higher levels of circulating FGF21, alongside elevated energy expenditure and insulin sensitivity. Evidence is emerging, however, that hepatic FGF21 can also be regulated by NEAA supply.…”

Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21

“…The liver is the most significant site of FGF21 production (3), and genetic studies in mice have demonstrated that circulating FGF21 is mostly derived from hepatocytes (22). It is believed that FGF21 in these conditions has a protective role via modulation of hepatic lipid metabolism and amelioration of endoplasmic reticulum stress (8,13,14). At the same time, elevated hepatic FAP expression has been observed in activated stellate cells in livers with cirrhosis (33,47).…”

“…Supraphysiological exposure to recombinant FGF21 or its engineered analogs ameliorates obesity, insulin resistance, dyslipidemia, fatty liver, and hyperglycemia in rodents (5,6). In mice, the metabolic activity of FGF21 is attributed to the stimulation of thermogenesis in brown adipose tissues (5,6), white adipose tissue browning (7), hepatic fatty acid oxidation (8), amelioration of hepatic endoplasmic reticulum stress (9), and induction of the adipokine adiponectin (10,11). Mice lacking FGF21 are refractory to diet-induced energy expenditure (12) and prone to developing NASH (8,13,14).…”

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

“…For example, anti-drug antibodies against a mutant FGF21 have the potential to cross-react and neutralize the endogenous FGF21 protein leading to autoimmune FGF21-deficiencies. FGF21 deficient mice are viable, but exhibit a heightened pathology when acute pancreatitis or non-alcoholic steatohepatitis is experimentally induced [64], [75], [76], [77]. Thus, the immunogenicity of each FGF21-analog should be carefully monitored during clinical studies.…”