G Protein-Coupled Receptor GPR35 Suppresses Lipid Accumulation in Hepatocytes

Abstract

Although prevalent, nonalcoholic fatty liver disease is not currently treated effectively with medicines. Initially, using wild-type and genome-edited clones of the human hepatocyte cell line HepG2, we show that activation of the orphan G protein-coupled receptor GPR35 is both able and sufficient to block liver X-receptor-mediated lipid accumulation. Studies on hepatocytes isolated from both wild-type and GPR35 knock-out mice were consistent with a similar effect of GPR35 agonists in these cells, but because of marked differences in the pharmacology of GPR35 agonists and antagonists at the mouse and human orthologues, as well as elevated basal lipid levels in hepatocytes from the GPR35 knock-out mice, no definitive conclusion could be reached. To overcome this, we generated and characterized a transgenic knock-in mouse line in which the corresponding human GPR35 splice variant replaced the mouse orthologue. In hepatocytes from these humanized GPR35 mice, activation of this receptor was shown conclusively to prevent, and also reverse, lipid accumulation induced by liver X-receptor stimulation. These studies highlight the potential to target GPR35 in the context of fatty liver diseases.

Identification of GPR35-associated metabolic characteristics through LC-MS/MS-based metabolomics and lipidomics

“…Therefore, we hypothesized that GPR35 might affect FAO by activating HIF-1α. In contrast, GPR35 might modulate the concentrations of relevant metabolites by affecting classic FAO targets, such as peroxisome proliferator-activated receptor [38], PGC-1α [19,39], and LXR [29,39]. For example, activated GPR35 up-regulates PGC-1α [19], and PGC-1α in turn increases FAO to meet energy requirements [39].…”

“…Dysregulation of PEs has been implicated in many metabolic diseases, such as atherosclerosis, insulin resistance, and obesity [43,44], as well as several chronic diseases, such as Alzheimer's disease, Parkinson's disease, and nonalcoholic liver disease [44,45]. GPR35 has also been implicated in type 2 diabetes mellitus [26,28] and nonalcoholic liver disease [29], among others. Furthermore, GPR35, through up-regulation of PGC-1α, significantly affects the expression of genes associated with lipid metabolism, thermogenesis, and anti-inflammation in adipose tissue [19].…”

“…Furthermore, GPR35 may act as an integration node in conditions in which inflammation skews metabolism, given that it is expressed in adipose tissue, immune cells, and the gastrointestinal tract, and that metabolic disorders often coincide with states of chronic inflammation [27]. Moreover, activation of GPR35 promotes lipid metabolism in skeletal muscle [28], adipose tissue [19], and liver cells [20,29]. However, little is known regarding the downstream metabolic characteristics upon GPR35 regulation.…”

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes

“…However, emerging evidence from experimental and clinical studies has linked altered hepatic cholesterol homeostasis and FC accumulation to NASH pathogenesis 9 , 10 . Several in vitro studies have indicated that GPR35 activation inhibits lipid accumulation in hepatocytes 50 , 51 . Nevertheless, the identity of the class of toxic lipids regulated by GPR35 and the mechanism are not known.…”

Isoforms of GPR35 have distinct extracellular N-termini that allosterically modify receptor-transducer coupling and mediate intracellular pathway bias

“…GPR35 represents the verified target of the mast-cell-stabilizing, approved antiallergic drug lodoxoamid (6) and is involved in a variety of physiological processes. GPR35 controls lipid metabolism and stimulates thermogenic programs in adipocytes as well as immune cell recruitment in different situations (7)(8)(9) while its function in the intestine is associated with inflammatory bowel disease, bacterial infection and oncogenic signaling (10)(11)(12)(13)(14)(15). In the heart, hypoxia-inducible factor-1 (HIF-1)mediated upregulation of GPR35 expression during cardiac infarction is associated with the disruption of the actin cytoskeleton arrangement and is suggested as an early marker of progressive cardiac failure (16,17).…”