Fructose‐1,6‐bisphosphatase deficiency causes fatty liver disease and requires long‐term hepatic follow‐up

Abstract

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver

“…Regression estimates were robust to multivariable adjustment, including metabolic risk factors, renal function, physical activity, and alcoholic drinks per week (relation of regression estimates across adjustments: Spearman π=0.95; P < 2.2×10 −16 ; Supplemental Figure 1 ). We observed significant enrichment of genes encoding the MASLD proteome in the liver ( Figure 2C ), specifying broad pathways implicated in central metabolic processes (e.g., carbon, pyruvate, amino acid, carbohydrate metabolism) and fibrosis ( Figure 2D ), including known and emerging mechanisms of MASLD, namely amino acid metabolism ( ACY1 6,11 , FAH 12 ), alcohol processing (e.g., ADH1A 13,14 ), fructose catabolism ( ALDOB, SORD 15 ), bile acid and steroid metabolism ( AKR1D1 16 , AKR1C4 17,18 ), gluconeogenesis ( FBP1 19 ), and multi-substrate detoxification, intermediary metabolism, and fibrosis ( GSTA1 20 , ASL 21 , UGDH 22 ), among others. To identify potential central mediators of MASLD, we next conducted an interaction (hub gene) analysis including 235 genes (of the 237 unique genes), with nodes identifying genes with central relevance to MASLD ( Figure 2E ).…”

FBP1 is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

“…Next, we examined whether PP2A-C and ALDOB were part of the AKT inhibitory mechanism triggered by FBP1. FBP1-deficient individuals exhibit mild hereditary fructose intolerance (HFI) (Gorce et al, 2022; Moey et al, 2018), a metabolic disorder associated with ALDOB deficiency (OMIM;229600), which blocks F1,6-P 2 breakdown (Herman and Birnbaum, 2021; Simons et al, 2019). ALDOB deficiency also causes hepatomegaly, hepatosteatosis and liver damage (Di Dato et al, 2019; Oppelt et al, 2015).…”

“…mTORC1 also activates the lipogenic transcription factor SREBP1c (Bakan and Laplante, 2012), accounting for increased lipogenesis and hyperlipidemia. Enhanced AKT activation may also contribute to some of the long-term metabolic abnormalities seen in older FBP1 deficient individuals (Gorce et al, 2022). Of note, hepatic FBP1 ablation in older (24-wo) Fbp1 F/F mice using AAV-CRE transduction resulted in pronounced liver damage, fibrosis and enhanced hepatocyte tumorigenesis, with a negligible effect on glucose tolerance (Li et al, 2020).…”

“…While not a direct target for insulin signaling, fructose (F) 1,6 bisphosphatase 1 (FBP1) is rate controlling for GNG, converting F1,6-P 2 to F6-P which is then converted to glucose (G) 6-P by phosphoglucoseisomerase (PGI) (Hunter et al, 2018; Li et al, 2014). FBP1 deficiency is a rare inborn metabolic error (OMIM:229700), that causes severe hypoglycemia, lactic acidosis, seizures, hepatomegaly, hyperlipidemia, hepatosteatosis and liver damage in carbohydrate starved, but not fed, infants (Gorce et al, 2022; Moey et al, 2018; Salih et al, 2020). While hypoglycemia and lactic acidosis are probably caused by low glycogen stores and abrogated GNG, there is no simple biochemical explanation for the hepatomegaly and elevated hepatic lipogenesis, which also affect non-starved older FBP1-deficient individuals (Gorce et al, 2022).…”

“…FBP1 deficiency is a rare inborn metabolic error (OMIM:229700), that causes severe hypoglycemia, lactic acidosis, seizures, hepatomegaly, hyperlipidemia, hepatosteatosis and liver damage in carbohydrate starved, but not fed, infants (Gorce et al, 2022; Moey et al, 2018; Salih et al, 2020). While hypoglycemia and lactic acidosis are probably caused by low glycogen stores and abrogated GNG, there is no simple biochemical explanation for the hepatomegaly and elevated hepatic lipogenesis, which also affect non-starved older FBP1-deficient individuals (Gorce et al, 2022). We investigated hepatocyte specific Fbp1 knockout mice ( Fbp1 ΔHep ), initially generated for understanding FBP1’s tumor suppressive function in hepatocellular carcinoma (HCC) (Li et al, 2020), and found that fasted Fbp1 ΔHep mice were phenotypically and metabolically identical to starved FBP1-deficient infants.…”